Akt inhibitors/activators

PI3K/Akt/mTOR

Isoform-selective Products

• All (80)
• Akt Inhibitors (66)
• Akt Activators (7)
• Akt Modulators (6)
• New Akt Products

Cat.No.	Product Name	Information	Product Use Citations	Product Validations
S1078	MK-2206 Dihydrochloride	MK-2206 2HCl is a highly selective inhibitor of Akt1/2/3 with IC50 of 8 nM/12 nM/65 nM in cell-free assays, respectively; no inhibitory activities against 250 other protein kinases observed. This compound induces autophagy and apoptosis in cancer cells. Phase 2.	Cell Res, 2025, 10.1038/s41422-025-01110-x Cell Res, 2025, 10.1038/s41422-025-01085-9 Mol Cancer, 2025, 24(1):272
S1037	Perifosine	Perifosine is a novel Akt inhibitor with IC50 of 4.7 μM in MM.1S cells, targets pleckstrin homology domain of Akt. Phase 3.	J Neuroinflammation, 2025, 22(1):32 Biomol Ther (Seoul), 2025, 33(1):170-181 iScience, 2024, 27(10):110862
S7863	SC79	SC79 is a brain-penetrable Akt phosphorylation activator and an inhibitor of Akt-PH domain translocation.	Nat Commun, 2025, 16(1):3734 J Immunother Cancer, 2025, 13(9)e010812 Int J Biol Sci, 2025, 21(5):2118-2134
S8019	Capivasertib (AZD5363)	Capivasertib (AZD5363) potently inhibits all isoforms of Akt(Akt1/Akt2/Akt3) with IC50 of 3 nM/8 nM/8 nM in cell-free assays, similar to P70S6K/PKA and lower activity towards ROCK1/2. This compound is in Phase 2.	Nat Commun, 2025, 16(1):8409 Cell Rep Med, 2025, 6(7):102192 EBioMedicine, 2025, 118:105828
S1113	GSK690693	GSK690693 is a pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 2 nM/13 nM/9 nM in cell-free assays, also sensitive to the AGC kinase family: PKA, PrkX and PKC isozymes. GSK690693 also potently inhibits AMPK and DAPK3 from the CAMK family with IC50 of 50 nM and 81 nM, respectively. GSK690693 affects Unc-51-like autophagy activating kinase 1 (ULK1) activity, robustly inhibits STING-dependent IRF3 activation. Phase 1.	Theranostics, 2025, 15(18):9819-9837 Cell Rep, 2025, 44(7):115947 Front Cell Infect Microbiol, 2025, 15:1543186
S2808	Ipatasertib (GDC-0068)	Ipatasertib (GDC-0068, RG7440) is a highly selective pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 5 nM/18 nM/8 nM in cell-free assays, demonstrating 620-fold selectivity over PKA. This compound is currently in Phase 2.	Oncogene, 2025, 44(44):4324-4337 Int J Mol Sci, 2025, 26(13)6139 Sci Rep, 2025, 15(1):35610
S1117	Triciribine (API-2)	Triciribine (API-2) is a DNA synthesis inhibitor that also inhibits Akt in PC3 cell line and HIV-1 in CEM-SS, H9, H9IIIB, U1 cells with IC50 of 130 nM and 20 nM, respectively; it does not inhibit PI3K/PDK1 and is 5000-fold less active in cells lacking adenosine kinase. Phase 1/2.	Mol Psychiatry, 2025, 10.1038/s41380-025-02917-1 Transl Oncol, 2025, 58:102434 J Cell Sci, 2023, 136(4)jcs259788
S2635	CCT128930	CCT128930 is a potent, ATP-competitive and selective inhibitor of Akt2 with IC50 of 6 nM in a cell-free assay, 28-fold greater selectivity for Akt2 than the closely related PKA kinase. This compound induces cell cycle arrest, DNA damage, and autophagy independent of Akt inhibition. High dose of this chemical triggers cell apoptosis in HepG2 cells.	Proc Natl Acad Sci U S A, 2025, 122(27):e2504962122 Cell Rep, 2025, 44(5):115625 Nat Commun, 2024, 15(1):6150
S7521	Afuresertib (GSK2110183)	Afuresertib (GSK2110183) is a potent, orally bioavailable Akt inhibitor with Ki values of 0.08 nM, 2 nM, and 2.6 nM for Akt1, Akt2, and Akt3, respectively, and is currently in Phase 2 trials.	Cell Rep, 2024, 43(9):114728 Oncogene, 2024, 43(19):1411-1430 EMBO Rep, 2024, 10.1038/s44319-024-00324-1
S2670	A-674563 HCl	A-674563 HCl is an Akt1 inhibitor with Ki of 11 nM in cell-free assays, modest potent to PKA and >30-fold selective for Akt1 over PKC.	Nat Commun, 2025, 16(1):3012 J Biol Chem, 2024, 300(2):105641 Nat Commun, 2023, 14(1):886
S1558	AT7867	AT7867 is a potent ATP-competitive inhibitor of Akt1/2/3 and p70S6K/PKA with IC50 of 32 nM/17 nM/47 nM and 85 nM/20 nM in cell-free assays, respectively; this compound shows little activity outside the AGC kinase family.	Exp Gerontol, 2023, 173:112091 Cancers (Basel), 2022, 14(21)5215 Oncoimmunology, 2021, 10(1):1943234
S2335	Oridonin	Oridonin, a diterpenoid purified from Rabdosia rubescens, is a traditional agent with antitumor, anti-bacterial and anti-inflammatory effects. This compound inhibits AKT1 and AKT2 kinase activity with IC50 of 8.4 μM and 8.9 μM, respectively.	Biochem Pharmacol, 2025, 242(Pt 2):117310 Invest Ophthalmol Vis Sci, 2025, 66(2):56 PLoS One, 2025, 20(9):e0333127
S7776	Akti-1/2	Akti-1/2 (Akt Inhibitor VIII) is a highly selective Akt1/Akt2 inhibitor with IC50 of 58 nM/210 nM, respectively, about 36-fold selectivity for Akt1 over Akt3. This compound induces apoptosis.	Nat Commun, 2025, 16(1):1313 Mol Metab, 2025, 100:102229 Life Sci Alliance, 2025, 8(11)e202503206
S1556	PHT-427	PHT-427 (CS-0223) is a dual Akt and PDPK1 inhibitor (high affinity binding for the PH domains of Akt and PDPK1) with Ki of 2.7 μM and 5.2 μM, respectively.	Exp Gerontol, 2023, 173:112091 Cancer Cell, 2022, S1535-6108(22)00312-9 Nucleic Acids Res, 2022, gkac179
S3056	Miltefosine	Miltefosine (Hexadecylphosphocholine) inhibits PI3K/Akt activity with ED50 of 17.2 μM and 8.1 μM in carcinoma cell lines A431 and HeLa, and is the first oral drug for Visceral leishmaniasis, effective against both promastigotes and amastigotes.	Front Pharmacol, 2025, 16:1496511 Biomol Ther (Seoul), 2025, 33(1):170-181 Res Vet Sci, 2025, 182:105467
S8339	Miransertib (ARQ 092) HCl	Miransertib (ARQ 092) HCl is a novel, orally bioavailable and selective AKT pathway inhibitor exhibiting a manageable safety profile among patients with advanced solid tumors.	World J Oncol, 2024, 15(2):192-208 Chemistry, 2023, e202203959. Nat Commun, 2022, 13(1):2111
S7563	AT13148	AT13148 is an oral, ATP-competitive, multi-AGC kinase inhibitor with IC50 of 38 nM/402 nM/50 nM, 8 nM, 3 nM, and 6 nM/4 nM for Akt1/2/3, p70S6K, PKA, and ROCKI/II, respectively. Phase 1.	Neoplasia, 2023, 10.1016/j.neo.2023.100948 Cancers (Basel), 2022, 14(23)5943 Br J Cancer, 2021, 10.1038/s41416-021-01442-6
S7492	Uprosertib (GSK2141795)	Uprosertib (GSK2141795, GSK795) is a selective, ATP-competitive, and orally bioavailable Akt inhibitor with IC50 of 180 nM, 328 nM, and 38 nM for Akt 1, 2 and 3, respectively. This compound is in Phase 2.	Nat Commun, 2022, 13(1):245 Bone Res, 2022, 10(1):27 Front Oncol, 2022, 12:905665
S6811	Miransertib (ARQ-092)	Miransertib (ARQ-092) is a potent, selective and orally bioavailable allosteric inhibitor of Akt with IC50s of 2.7 nM, 14 nM and 8.1 nM for Akt1, Akt2, Akt3, respectively.	World J Oncol, 2024, 15(3):492-505 World J Oncol, 2024, 15(2):192-208 Commun Biol, 2023, 6(1):916
S5313	SC66	SC66 is an allosteric inhibitor which displays a dual-inhibitory function toward AKT activity with IC50 values of 0.77, 2.85 and 0.47 μg/ml in HepG2, Huh7 and Hep3B cells after 72 h treatment, respectively.	Biomed Pharmacother, 2024, 177:117038 Chem Biol Interact, 2023, 10.1016/j.cbi.2023.110725 J Cell Mol Med, 2021, 10.1111/jcmm.17005
S8132	Deguelin	Deguelin, a natural product isolated from plants in the Mundulea sericea family, is an PI3K/AKT Inhibitor.	bioRxiv, 2025, 2025.04.25.650475 Cell, 2023, 186(13):2929-2949.e20 Cell Death Dis, 2020, 11(2):143
S6847	ML-9 HCl	ML-9 HCl (ML-9 hydrochloride) is a selective and potent inhibitor of Akt kinase, myosin light chain kinase (MLCK) and stromal interaction molecule 1 (STIM1). This compound is also a potent inhibitor of Ca2+-permeable channels. It is a lysosomotropic agent targeting autophagy and cell death.	Cell Mol Life Sci, 2025, 82(1):201 PLoS Pathog, 2023, 19(3):e1011295 J Mol Endocrinol, 2019, 63(3):199-213
S7127	TIC10 Analogue	TIC10 Analogue is an analogue of TIC10, which inactivates Akt and ERK to induce TRAIL through Foxo3a, possesses superior drug properties: delivery across the blood-brain barrier, superior stability and improved pharmacokinetics. Phase 1/2.	Cell Rep, 2025, 44(5):115619 Cancer Med, 2025, 14(14):e71061 PLoS One, 2024, 19(12):e0315037
E2947	Recilisib	Recilisib (ON01210, EX-RAD) is a radioprotectant that activates the activity of AKT and PI3K in cells. It has been studied as prophylactic (use prior to radiation exposure) and therapeutic (after exposure to radiation) drug.
S6982New	3CAI	3CAI inhibits AKT1 and AKT2.
S9514	Rotundic acid	Rotundic acid (Rutundic acid), a natural compound, exhibit cytotoxic activities toward human hepatocellular carcinoma (HepG2), malignant melanoma (A375), SCLC (NCI-H446), breast cancer (MCF-7), and colon cancer (HT-29) cell lines.RA induces cell cycle arrest, DNA damage, and apoptosis by modulating the AKT/mTOR and MAPK pathways.
S8839	Borussertib	Borussertib is a covalent-allosteric inhibitor of protein kinase Akt with an IC50 of 0.8 nM and a Ki of 2.2 nM for WT Akt.
E1125	A-443654	A-443654, a derivative of indazole–pyridine compounds, is a pan Akt (Akt1, 2, & 3 isoforms) inhibitor which binds to the ATP-binding site of Akt. It is an ATP competitive and reversible inhibitor.
S4953	Usnic acid	Usnic acid (Usniacin) is a furandione found uniquely in lichen that is used widely in cosmetics, deodorants, toothpaste and medicinal creams as well as some herbal products. It exhibits antiviral, antiprotozoal, antiproliferative, anti-inflammatory and analgesic activity. This compound inhibits breast tumor angiogenesis and growth by suppressing VEGFR2-mediated AKT and ERK1/2 signaling pathways.
E1710	LY2780301	LY2780301 is a highly selective adenosine triphosphate (ATP)-competitive dual inhibitor of p70S6K and Akt. This compound binds to Akt, inhibiting its activity, which consequently blocks the PI3K/Akt signaling pathway which leads to reduced cell proliferation and the initiation of apoptosis in tumor cells.
E3241	Cinnamomi Ramulus Extract	Cinnamomi Ramulus Extract is extracted from Cinnamomi Ramulus, which can inhibit the growth of colon cancer cells via Akt/ERK signaling pathways.
E3041	Alpiniae Katsumadai Extract	Alpiniae Katsumadai Extract is extracted from Alpiniae Katsumadai, which can induce growth inhibition and autophagy‑related apoptosis by regulating the AMPK and Akt/mTOR/p70S6K signaling pathways in cancer cells.
S9315	Praeruptorin A	Praeruptorin A, a naturally existing pyranocumarin, is isolated from the dried root of Peucedanum praeruptorum Dunn. This compound inhibits p38/Akt-c-Fos-NFATc1 signaling and PLCγ-independent Ca2+ oscillation. It can significantly upregulates multidrug resistance-associated protein 2 expression via the constitutive androstane receptor-mediated pathway in vitro, and this should be taken as an herb-drug interaction.
E3365	Weigela Grandiflora Fortune Extract	Weigela Grandiflora Fortune Extract is extracted from Weigela Grandiflora Fortune, which decreases the infection-mediated expression of inflammatory mediators by inhibiting the AKT/NF-κB and MAPK signaling pathways.
E4992	Afuresertib hydrochloride	Afuresertib hydrochloride (GSK 2110183 hydrochloride, LAE002 hydrochloride) is an orally bioavailable, selective, ATP-competitive and potent inhibitor of pan-Akt kinase with Ki values of 0.08 nM, 2 nM, 2.6 nM for Akt1/Akt2/Akt3 respectively.
E5820	AKT Kinase Inhibitor	AKT Kinase Inhibitor is an inhibitor of Akt that reverses the protective effects of Tadalafil (TAD) in LPS-induced RWPE-1 cells by decreasing cell viability, promoting apoptosis, and increasing pro-inflammatory cytokine levels.
S2323	Methyl-Hesperidin	Methyl Hesperidin is a flavanone glycoside (flavonoid) (C28H34O15) found abundantly in citrus fruits. Its aglycone form is called hesperetin.
E7359	A-674563	A-674563 is a selective, orally active inhibitor of Akt1 with a Ki of 11 nM. It also inhibits PKA with Ki of 16 nM and CDK2 with Ki of 46 nM. This compound reduces Akt downstream target phosphorylation and inhibits tumor cell proliferation in vitro with an EC50 of 0.4 µM.
S8500	BAY1125976	BAY 1125976 is a selective allosteric AKT1/2 inhibitor, exhibits high efficacy on AKT signaling-dependent tumor growth in mouse models. This compound inhibits the activity of AKT1 (IC50 = 5.2 nM at 10 µM ATP and 44 nM at 2 mM ATP) and AKT2 (IC50 = 18 nM at 10 µM ATP and 36 nM at 2 mM ATP) very potently. Whereas this chemical is almost inactive on AKT3 (IC50 = 427 nM at 10 µM ATP).
S9611	ABTL-0812	ABTL0812 (α-Hydroxylinoleic acid, LP-10218, SCLN-0812) inhibits Akt/mTOR axis by inducing the overexpression of TRIB3 and activating autophagy in lung squamous carcinoma cell lines. ABTL0812 also induces AMPK activation and ROS accumulation.
E5971New	ZINC00640089	ZINC00640089 is a selective Lipocalin-2 (LCN2) inhibitor that suppresses cell proliferation, decreases cell viability, and reduces AKT phosphorylation levels in SUM149 cells. This compound shows promising research potential for inflammatory breast cancer (IBC) studies.
S3241	Loureirin A	Loureirin A is a flavonoid extracted from the red resin of the herbs of Dracaena cochinchinensis, which is known as Dragon's Blood. This compound inhibits platelet activation by an impairment of PI3K/Akt signaling. It also inhibits Akt phosphorylation.
E1604	Vevorisertib trihydrochloride	Vevorisertib trihydrochloride(ARQ 751 trihydrochloride) is a selective, allosteric inhibitor of pan-AKT and AKT1-E17K mutant with Kd values of 1.2 nM and 8.6 nM, respectively. It also has IC50 values of 0.55, 0.81, and 1.3 nM for AKT1, AKT2, and AKT3, respectively and can be used for the research of cancer.
S2743	PF-04691502	PF-04691502 (PF4691502) is an ATP-competitive PI3K(α/β/δ/γ)/mTOR dual inhibitor with Ki of 1.8 nM/2.1 nM/1.6 nM/1.9 nM and 16 nM in cell-free assays, little activity against either Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK. This compound induces apoptosis. Phase 2.	Cell Death Discov, 2025, 11(1):266 Exp Gerontol, 2024, 186:112359 iScience, 2023, 26(9):107734
S1362	Rigosertib (ON-01910)	Rigosertib (ON-01910) is a non-ATP-competitive inhibitor of PLK1 with IC50 of 9 nM in a cell-free assay, showing 30-fold greater selectivity against Plk2 and no activity to Plk3. It inhibits the PI3K/Akt pathway, activates oxidative stress signals, and induces apoptosis in various cancer cells. This compound is in Phase 3.	Drug Resist Updat, 2025, 81:101251 Drug Resist Updat, 2025, 81:101251 Nat Commun, 2024, 15(1):2089
S2310	Honokiol	Honokiol is the active principle of magnolia extract that inhibits Akt-phosphorylation and promotes ERK1/2 phosphorylation. This compound causes G0/G1 phase arrest, induces apoptosis, and autophagy via the ROS/ERK1/2 signaling pathway. It inhibits hepatitis C virus (HCV) infection. Phase 3.	J Adv Res, 2025, S2090-1232(25)00062-1 J Nanobiotechnology, 2025, 23(1):414 Oncol Lett, 2025, 29(4):191
S5144	Neferine	Neferine ((R)-1,2-Dimethoxyaporphine), a natural component of Nelumbo nucifera, has antitumor efficiency. It induces apoptosis in renal cancer cells. This compound prevents autophagy through activation of Akt/mTOR pathway and Nrf2 in muscle cells. It strongly inhibits NF-κB activation. It possesses a number of therapeutic effects such as anti-diabetic, anti-aging, anti-microbial, anti-thrombotic, anti-arrhythmic, anti-inflammatory and even anti-HIV.	J Cosmet Dermatol, 2024, 10.1111/jocd.16587 Bone Res, 2022, 10(1):27 Cell Death Dis, 2022, 13(11):1000
S3901	Astragaloside IV	Astragaloside IV (AST-IV, AS-IV) is a bioactive saponin first isolated from the dried plant roots of the genus Astragalus, which is used in traditional Chinese medicine. It has various effect on the cardiovascular, immune, digestive, and nervous systems. AS-IV suppresses activation of p-Akt, p-mTOR, p-NF-κB and p-Erk1/2.	Cell Transplant, 2023, 32:9636897231198167 Cell Transplant, 2023, 32:9636897231198167 Cell Cycle, 2022, 1-14
S9190	Oroxin B	Oroxin B (Hypocretin-2), one of flavonoids isolated from traditional Chinese herbal medicine Oroxylum indicum (L.) Vent, selectively induces tumor-suppressive ER stress in malignant lymphoma cells and has antioxidant activity. This compound significantly inhibits proliferation and induce apoptosis, which may be strongly associated with the inhibiting COX-2/VEGF and PTEN/PI3K/AKT signaling pathway in SMMC-7721 cells, it potentially be used as a novel therapeutic agent for liver cancer.COX-2, VEGF, PI3K, and p-AKT expression levels are downregulated, while PTEN is upregulated after this chemical treatment.	Environ Pollut, 2023, 323:121306 Theranostics, 2022, 12(2):910-928 J Cancer, 2021, 12(7):2140-2150
S3238	Resibufogenin	Resibufogenin (Bufogenin, Recibufogenin), a component of huachansu with anticancer effect, triggers necroptosis through upregulating receptor-interacting protein kinase 3 (RIP3) and phosphorylating mixed lineage kinase domain-like protein at Ser358. This compound exerts cytotoxic effect by inducing reactive oxygen species (ROS) accumulation. It induces apoptosis and caspase-3 and caspase-8 activity. This chemical increases Bax/Bcl-2 expression, and suppresses cyclin D1, cyclin E, PI3K, p-AKT, p-GSK3β and β-catenin protein expression.	bioRxiv, 2025, 2025.07.17.665404 Research Square, 2024, 10.21203/rs.3.rs-3790060/v1 Phytomedicine, 2022, 102:154182
S3296	Hispidulin	Hispidulin (Dinatin), an active natrual ingredient in a number of traditional Chinese medicinal herbs, exhibits inhibitory activity against the oncogenic protein kinase Pim-1 with IC50 of 2.71 μM. This compound induces apoptosis through mitochondrial dysfunction and inhibition of P13k/Akt signalling pathway in HepG2 cancer cells. It exerts anti-osteoporotic and bone resorption attenuating effects via activating the AMPK signaling pathway.	Evid Based Complement Alternat Med, 2023, 2023:9428241
E2384	(E)-Akt inhibitor-IV	(E)-Akt inhibitor-IV is a PI3K-Akt inhibitor, with potent cytotoxic.	Res Sq, 2025, rs.3.rs-5931887 Eur J Pharmacol, 2022, 931:175186
S3785	Notoginsenoside R1	Notoginsenoside R1 (Sanchinoside R1) is the main ingredient with cardiovascular activity in Panax notoginseng. It inhibits TNF-α-induced PAI-1 overexpression via extracellular signal-related kinases (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling pathways.	Food Sci Nutr, 2023, 11(12):7791-7802 J Ethnopharmacol, 2021, S0378-8741(21)00169-0
S3810	Scutellarin	Scutellarin (Breviscapine, Breviscapin, Scutellarein-7-glucuronide), the major active principal flavonoids extracted from the Chinese herbal medicines Scutellaria baicalensis and Erigeron breviscapus (Vant.) Hand-Mazz, has many pharmacological effects, such as antioxidant, antitumor, antiviral, and antiinflammatory activities. This compound can down-regulates the STAT3/Girdin/Akt signaling in HCC cells, and inhibits RANKL-mediated MAPK and NF-κB signaling pathway in osteoclasts.	Biomed Pharmacother, 2022, 155:113781
S3220	Trigonelline	Trigonelline (Trigenolline) is a plant alkaloid and a major component of coffee and fenugreek with anti-degranulation, anti-diabetic, antioxidant, anti-inflammatory, and neuroprotective effects. This compound inhibits FcεRI-mediated intracellular signaling pathways, such as phosphorylation of PLCγ1, PI3K, and Akt. It also inhibits the microtubule formation in RBL-2H3 cells.	Int J Med Sci, 2025, 22(5):1194-1207 Biochem Biophys Rep, 2025, 42:102021 Biomed Pharmacother, 2021, 143:112204
S3294	Demethyl-Coclaurine	Demethyl-Coclaurine (Higenamine, Norcoclaurine), the key component of the Chinese herb aconite root, is a beta-2 adrenergic receptor (β2-AR) agonist. This compound stimulates AKT phosphorylation and requires PI3K activation for the anti-apoptotic effect in cardiomyocytes.	Signal Transduct Target Ther, 2024, 9(1):243
S4572	Homosalate	Homosalate (HMS, Homomenthyl salicylate) is an organic ultraviolet filter used in most sunscreens but has been reported to be toxic to marine organisms. This compound aggravates the invasion of human trophoblast cells as well as regulates intracellular signaling pathways including PI3K/AKT and MAPK pathways.
S3289	Daphnoretin	Daphnoretin (Dephnoretin, Thymelol), a biologically active compound isolated from Wikstroemia indica C.A. Mey., is a protein kinase C (PKC) activator. This compound inhibits the proliferation, invasion, and migration of tumor cells and promote its apoptosis by regulating the activity of Akt signal pathway.
S3224	Cinobufagin	Cinobufagin (Cinobufagine), an active ingredient of Venenum Bufonis, inhibits tumor development. This compound increases ATM and Chk2 and decreases CDC25C, CDK1, and cyclin B. It inhibits PI3K, AKT and Bcl-2 while increases levels of cleaved caspase-9 and caspase-3. Thus, this chemical induces cell cycle arrest at the G2/M phase and apoptosis.
S8961	Alobresib (GS-5829)	Alobresib (GS-5829) is a novel BET inhibitor that represents a highly effective therapeutics agent against recurrent/chemotherapy-resistant USC-overexpressing c-Myc. This compound inhibits CLL cell proliferation and induces leukemia cell apoptosis through deregulation of key signaling pathways, such as BLK, AKT, ERK1/2, and MYC. It also inhibits NF-κB signaling.
S5554	Lanatoside C	Lanatoside C is a cardiac glycoside with antiviral and anti-tumor activity. This compound induces G2/M cell cycle arrest and induces autophagy and apoptosis via attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR signaling pathways.
S3243	Zeaxanthin	Zeaxanthin, the carotenoid alcohol participates in the xanthophyll cycle, activates the extrinsic apoptosis pathway which induces apoptosis on uveal melanoma cells with IC50 value 40.8 µM.
E3656	Dichroa febrifuga Extract	Dichroa Febrifuga Extract is extracted from Dichroa Febrifuga, which can Suppress PI3K/AKT and MAPK Signaling Pathways.
S0765	MAZ51	MAZ51 is a potent and selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-3 (Flt-4) tyrosine kinase. This compound induces cell rounding and G2/M cell cycle arrest in glioma cells through phosphorylation of Akt/GSK3β and activation of RhoA. It inhibits the proliferation and induces the apoptosis of a variety of non-VEGFR-3-expressing tumor cell lines.	Sci Rep, 2025, 15(1):1283
E4864	Pentamidine	Pentamidine (MP-601205) is an aromatic diamidine drug, an antagonist of TLR4.It also inhibits PI3K/AKT signaling pathway and reduce the expression of MMP-2 and MMP-9. It exhibits anti- protozoal, anti-inflammatory, and anti-tumor activities and is used as an agent for treating African trypanosomiasis, antimony resistant leishmaniasis and Pneumocystis carinii pneumonia.
E3106	Dioscoreae Nipponicae Rhizoma Extract	Dioscoreae Nipponicae Rhizoma Extract is extracted from the rhizome of Dioscorea nipponica, of which the main component decreases the phosphorylation in IGF-1R, which in turn inhibits the phosphorylation and activation of PI3K-AKT and Rap1-MEK signaling pathways, promoting cell apoptosis and Graves’ disease remission.
E0020	Lupenone	Lupenone (Lup-20(29)-en-3-one, lupeone) is an isolated compound exhibiting anti-oxidative, anti-inflammation, and anti-diabetic activities. This compound can protect SH-SY5y cells against METH-induced neuronal apoptosis through the PI3K/Akt pathway.
S2298	Fisetin	Fisetin (Fustel) is a potent sirtuin activating compound (STAC) and an agent that modulates sirtuins.	Sci Adv, 2025, 11(17):eads1875 Mol Cancer, 2024, 23(1):222 Cell Death Dis, 2024, 15(8):608
S6760	LM22B-10	LM22B-10 is a small molecule TrkB/TrkC neurotrophin receptor co-activator. This compound selectively activates TrkB, TrkC, AKT and ERK in vivo and in vitro.	Theranostics, 2024, 14(4):1561-1582 Int J Mol Sci, 2024, 25(4)2408 Sci Rep, 2024, 14(1):12090
S3309	Solasodine	Solasodine (Purapuridine, Solancarpidine, Solasodin, Salasodine, Salasdine) is a poisonous alkaloid chemical compound that occurs in plants of the Solanaceae family. This compound reduces the mRNA level of matrix metalloproteinase-2 (MMP-2), MMP-9 and extracellular inducer of matrix metalloproteinase (EMMPRIN), but increases the expression of reversion-inducing cysteine-rich protein with kazal motifs (RECK). It downregulates oncogenic microRNA-21 (miR-21), which has been known to target RECK. This chemical also reduces PI3K/Akt signaling pathways and downregulates expression of miR-21.
S9054	Pectolinarin	Pectolinarin is a major compound in Cirsium setidens with anti-inflammatory activity. This compound inhibits secretion of IL-6 and IL-8, as well as the production of PGE2 and NO. It also induces apoptosis via inactivation of the PI3K/Akt pathway.
E2391	α-Linolenic acid	α-Linolenic acid, an essential fatty acid isolated from seed oils, affects the process of thrombotic through the modulation of PI3K/Akt signaling, and possesses the anti-arrhythmic properties.
E0945	BIA	BIA (TMBIM6 antagonist BIA), a potential TMBIM6 antagonist, is an inhibitor of the interaction between TMBIM6 (Transmembrane B cell lymphoma 2-associated X protein (BAX) inhibitor motif-containing 6) and mTORC2, which ultimately blocks AKT activation and cancer progression.
S6885	Ailanthone	Ailanthone (AIL, Δ13-Dehydrochaparrinone), a natural anti-hepatocellular carcinoma (HCC) component in Ailanthus altissima, induces G0/G1-phase cell cycle arrest by decreasing expression of cyclins and CDKs and increases expression of p21 and p27. This compound triggers DNA damage characterized by activation of the ATM/ATR pathway. It induces apoptosis which is mitochondrion-mediated and involves the PI3K/AKT signaling pathway in Huh7 cells. This chemical is also a potent inhibitor of both full-length Androgen Receptor (AR-FL) and constitutively active truncated AR splice variants (AR-Vs, AR1-651) with IC50 of 69 nM and 309 nM, respectively.	Theranostics, 2024, 14(4):1371-1389
E2682	RPI-1	RPI-1 inhibits proliferation of human papillary thyroid carcinoma cell line TPC-1 by inducing accumulation of cells at the G2 cell cycle phase, abolishes Ret/Ptc1 tyrosine phosphorylation along with its binding to Shc and phospholipase Cg, also abolishes the activation of JNK2 and AKT.
E2826	Hematein	Hematein inhibits casein kinase II activity in a selective, dose-dependent and ATP non-competitive manner in vitro, with IC50 of 0.55 μM in the presence of 10 μM ATP.
E2401	SPP-86	SPP-86, a potent and selective cell permeable inhibitor of rearranged during transfection (RET) tyrosine kinase with an IC50 of 8 nM, inhibits RET-induced phosphatidylinositide 3-kinases (PI3K)/Akt and MAPK signaling, also inhibits RET-induced estrogen receptorα (ERα) phosphorylation in MCF7 cells.
S1321	Urolithin B	Urolithin B inhibits NF-κB activity by reducing the phosphorylation and degradation of IκBα. This compound suppresses the phosphorylation of JNK, ERK, and Akt, and enhances the phosphorylation of AMPK. It is also a regulator of skeletal muscle mass.	PLoS Pathog, 2025, 21(8):e1013401
S1273	Amarogentin	Amarogentin (AG), a secoiridoid glycoside mainly extracted from Swertia and Gentiana roots, exhibits anti-oxidative, anti-tumour, and anti-diabetic activities. This compound is an agonist for the bitter taste receptor TAS2R1 and inhibits in LAD-2 cells substance P-induced production of newly synthesized TNF-α. It induces apoptosis in human gastric cancer cells (SNU-16) through G2/M cell cycle arrest and PI3K/Akt signalling pathway. This chemical interacts with the α2 subunit of AMP-activated protein kinase (AMPK) and activates the trimeric kinase with EC50 of 277 pM.
E0785	YS-49	YS-49 is a PI3K/Akt (a downstream target of RhoA) activator, to reduce RhoA/PTEN activation in the 3-methylcholanthrene-treated cells, inhibits angiotensin II (Ang II)-stimulated proliferation of VSMCs via induction of heme oxygenase (HO)-1, also is an isoquinoline compound alkaloid, has a strong positive inotropic action through activation of cardiac β-adrenoceptors.	Cell Signal, 2025, 131:111752 Signal Transduct Target Ther, 2024, 9(1):243
S1078	MK-2206 Dihydrochloride	MK-2206 2HCl is a highly selective inhibitor of Akt1/2/3 with IC50 of 8 nM/12 nM/65 nM in cell-free assays, respectively; no inhibitory activities against 250 other protein kinases observed. This compound induces autophagy and apoptosis in cancer cells. Phase 2.	Cell Res, 2025, 10.1038/s41422-025-01110-x Cell Res, 2025, 10.1038/s41422-025-01085-9 Mol Cancer, 2025, 24(1):272
S1037	Perifosine	Perifosine is a novel Akt inhibitor with IC50 of 4.7 μM in MM.1S cells, targets pleckstrin homology domain of Akt. Phase 3.	J Neuroinflammation, 2025, 22(1):32 Biomol Ther (Seoul), 2025, 33(1):170-181 iScience, 2024, 27(10):110862
S8019	Capivasertib (AZD5363)	Capivasertib (AZD5363) potently inhibits all isoforms of Akt(Akt1/Akt2/Akt3) with IC50 of 3 nM/8 nM/8 nM in cell-free assays, similar to P70S6K/PKA and lower activity towards ROCK1/2. This compound is in Phase 2.	Nat Commun, 2025, 16(1):8409 Cell Rep Med, 2025, 6(7):102192 EBioMedicine, 2025, 118:105828
S1113	GSK690693	GSK690693 is a pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 2 nM/13 nM/9 nM in cell-free assays, also sensitive to the AGC kinase family: PKA, PrkX and PKC isozymes. GSK690693 also potently inhibits AMPK and DAPK3 from the CAMK family with IC50 of 50 nM and 81 nM, respectively. GSK690693 affects Unc-51-like autophagy activating kinase 1 (ULK1) activity, robustly inhibits STING-dependent IRF3 activation. Phase 1.	Theranostics, 2025, 15(18):9819-9837 Cell Rep, 2025, 44(7):115947 Front Cell Infect Microbiol, 2025, 15:1543186
S2808	Ipatasertib (GDC-0068)	Ipatasertib (GDC-0068, RG7440) is a highly selective pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 5 nM/18 nM/8 nM in cell-free assays, demonstrating 620-fold selectivity over PKA. This compound is currently in Phase 2.	Oncogene, 2025, 44(44):4324-4337 Int J Mol Sci, 2025, 26(13)6139 Sci Rep, 2025, 15(1):35610
S1117	Triciribine (API-2)	Triciribine (API-2) is a DNA synthesis inhibitor that also inhibits Akt in PC3 cell line and HIV-1 in CEM-SS, H9, H9IIIB, U1 cells with IC50 of 130 nM and 20 nM, respectively; it does not inhibit PI3K/PDK1 and is 5000-fold less active in cells lacking adenosine kinase. Phase 1/2.	Mol Psychiatry, 2025, 10.1038/s41380-025-02917-1 Transl Oncol, 2025, 58:102434 J Cell Sci, 2023, 136(4)jcs259788
S2635	CCT128930	CCT128930 is a potent, ATP-competitive and selective inhibitor of Akt2 with IC50 of 6 nM in a cell-free assay, 28-fold greater selectivity for Akt2 than the closely related PKA kinase. This compound induces cell cycle arrest, DNA damage, and autophagy independent of Akt inhibition. High dose of this chemical triggers cell apoptosis in HepG2 cells.	Proc Natl Acad Sci U S A, 2025, 122(27):e2504962122 Cell Rep, 2025, 44(5):115625 Nat Commun, 2024, 15(1):6150
S7521	Afuresertib (GSK2110183)	Afuresertib (GSK2110183) is a potent, orally bioavailable Akt inhibitor with Ki values of 0.08 nM, 2 nM, and 2.6 nM for Akt1, Akt2, and Akt3, respectively, and is currently in Phase 2 trials.	Cell Rep, 2024, 43(9):114728 Oncogene, 2024, 43(19):1411-1430 EMBO Rep, 2024, 10.1038/s44319-024-00324-1
S2670	A-674563 HCl	A-674563 HCl is an Akt1 inhibitor with Ki of 11 nM in cell-free assays, modest potent to PKA and >30-fold selective for Akt1 over PKC.	Nat Commun, 2025, 16(1):3012 J Biol Chem, 2024, 300(2):105641 Nat Commun, 2023, 14(1):886
S1558	AT7867	AT7867 is a potent ATP-competitive inhibitor of Akt1/2/3 and p70S6K/PKA with IC50 of 32 nM/17 nM/47 nM and 85 nM/20 nM in cell-free assays, respectively; this compound shows little activity outside the AGC kinase family.	Exp Gerontol, 2023, 173:112091 Cancers (Basel), 2022, 14(21)5215 Oncoimmunology, 2021, 10(1):1943234
S2335	Oridonin	Oridonin, a diterpenoid purified from Rabdosia rubescens, is a traditional agent with antitumor, anti-bacterial and anti-inflammatory effects. This compound inhibits AKT1 and AKT2 kinase activity with IC50 of 8.4 μM and 8.9 μM, respectively.	Biochem Pharmacol, 2025, 242(Pt 2):117310 Invest Ophthalmol Vis Sci, 2025, 66(2):56 PLoS One, 2025, 20(9):e0333127
S7776	Akti-1/2	Akti-1/2 (Akt Inhibitor VIII) is a highly selective Akt1/Akt2 inhibitor with IC50 of 58 nM/210 nM, respectively, about 36-fold selectivity for Akt1 over Akt3. This compound induces apoptosis.	Nat Commun, 2025, 16(1):1313 Mol Metab, 2025, 100:102229 Life Sci Alliance, 2025, 8(11)e202503206
S1556	PHT-427	PHT-427 (CS-0223) is a dual Akt and PDPK1 inhibitor (high affinity binding for the PH domains of Akt and PDPK1) with Ki of 2.7 μM and 5.2 μM, respectively.	Exp Gerontol, 2023, 173:112091 Cancer Cell, 2022, S1535-6108(22)00312-9 Nucleic Acids Res, 2022, gkac179
S3056	Miltefosine	Miltefosine (Hexadecylphosphocholine) inhibits PI3K/Akt activity with ED50 of 17.2 μM and 8.1 μM in carcinoma cell lines A431 and HeLa, and is the first oral drug for Visceral leishmaniasis, effective against both promastigotes and amastigotes.	Front Pharmacol, 2025, 16:1496511 Biomol Ther (Seoul), 2025, 33(1):170-181 Res Vet Sci, 2025, 182:105467
S8339	Miransertib (ARQ 092) HCl	Miransertib (ARQ 092) HCl is a novel, orally bioavailable and selective AKT pathway inhibitor exhibiting a manageable safety profile among patients with advanced solid tumors.	World J Oncol, 2024, 15(2):192-208 Chemistry, 2023, e202203959. Nat Commun, 2022, 13(1):2111
S7563	AT13148	AT13148 is an oral, ATP-competitive, multi-AGC kinase inhibitor with IC50 of 38 nM/402 nM/50 nM, 8 nM, 3 nM, and 6 nM/4 nM for Akt1/2/3, p70S6K, PKA, and ROCKI/II, respectively. Phase 1.	Neoplasia, 2023, 10.1016/j.neo.2023.100948 Cancers (Basel), 2022, 14(23)5943 Br J Cancer, 2021, 10.1038/s41416-021-01442-6
S7492	Uprosertib (GSK2141795)	Uprosertib (GSK2141795, GSK795) is a selective, ATP-competitive, and orally bioavailable Akt inhibitor with IC50 of 180 nM, 328 nM, and 38 nM for Akt 1, 2 and 3, respectively. This compound is in Phase 2.	Nat Commun, 2022, 13(1):245 Bone Res, 2022, 10(1):27 Front Oncol, 2022, 12:905665
S6811	Miransertib (ARQ-092)	Miransertib (ARQ-092) is a potent, selective and orally bioavailable allosteric inhibitor of Akt with IC50s of 2.7 nM, 14 nM and 8.1 nM for Akt1, Akt2, Akt3, respectively.	World J Oncol, 2024, 15(3):492-505 World J Oncol, 2024, 15(2):192-208 Commun Biol, 2023, 6(1):916
S5313	SC66	SC66 is an allosteric inhibitor which displays a dual-inhibitory function toward AKT activity with IC50 values of 0.77, 2.85 and 0.47 μg/ml in HepG2, Huh7 and Hep3B cells after 72 h treatment, respectively.	Biomed Pharmacother, 2024, 177:117038 Chem Biol Interact, 2023, 10.1016/j.cbi.2023.110725 J Cell Mol Med, 2021, 10.1111/jcmm.17005
S8132	Deguelin	Deguelin, a natural product isolated from plants in the Mundulea sericea family, is an PI3K/AKT Inhibitor.	bioRxiv, 2025, 2025.04.25.650475 Cell, 2023, 186(13):2929-2949.e20 Cell Death Dis, 2020, 11(2):143
S6847	ML-9 HCl	ML-9 HCl (ML-9 hydrochloride) is a selective and potent inhibitor of Akt kinase, myosin light chain kinase (MLCK) and stromal interaction molecule 1 (STIM1). This compound is also a potent inhibitor of Ca2+-permeable channels. It is a lysosomotropic agent targeting autophagy and cell death.	Cell Mol Life Sci, 2025, 82(1):201 PLoS Pathog, 2023, 19(3):e1011295 J Mol Endocrinol, 2019, 63(3):199-213
S7127	TIC10 Analogue	TIC10 Analogue is an analogue of TIC10, which inactivates Akt and ERK to induce TRAIL through Foxo3a, possesses superior drug properties: delivery across the blood-brain barrier, superior stability and improved pharmacokinetics. Phase 1/2.	Cell Rep, 2025, 44(5):115619 Cancer Med, 2025, 14(14):e71061 PLoS One, 2024, 19(12):e0315037
S6982New	3CAI	3CAI inhibits AKT1 and AKT2.
S8839	Borussertib	Borussertib is a covalent-allosteric inhibitor of protein kinase Akt with an IC50 of 0.8 nM and a Ki of 2.2 nM for WT Akt.
E1125	A-443654	A-443654, a derivative of indazole–pyridine compounds, is a pan Akt (Akt1, 2, & 3 isoforms) inhibitor which binds to the ATP-binding site of Akt. It is an ATP competitive and reversible inhibitor.
S4953	Usnic acid	Usnic acid (Usniacin) is a furandione found uniquely in lichen that is used widely in cosmetics, deodorants, toothpaste and medicinal creams as well as some herbal products. It exhibits antiviral, antiprotozoal, antiproliferative, anti-inflammatory and analgesic activity. This compound inhibits breast tumor angiogenesis and growth by suppressing VEGFR2-mediated AKT and ERK1/2 signaling pathways.
E1710	LY2780301	LY2780301 is a highly selective adenosine triphosphate (ATP)-competitive dual inhibitor of p70S6K and Akt. This compound binds to Akt, inhibiting its activity, which consequently blocks the PI3K/Akt signaling pathway which leads to reduced cell proliferation and the initiation of apoptosis in tumor cells.
E3241	Cinnamomi Ramulus Extract	Cinnamomi Ramulus Extract is extracted from Cinnamomi Ramulus, which can inhibit the growth of colon cancer cells via Akt/ERK signaling pathways.
E3041	Alpiniae Katsumadai Extract	Alpiniae Katsumadai Extract is extracted from Alpiniae Katsumadai, which can induce growth inhibition and autophagy‑related apoptosis by regulating the AMPK and Akt/mTOR/p70S6K signaling pathways in cancer cells.
S9315	Praeruptorin A	Praeruptorin A, a naturally existing pyranocumarin, is isolated from the dried root of Peucedanum praeruptorum Dunn. This compound inhibits p38/Akt-c-Fos-NFATc1 signaling and PLCγ-independent Ca2+ oscillation. It can significantly upregulates multidrug resistance-associated protein 2 expression via the constitutive androstane receptor-mediated pathway in vitro, and this should be taken as an herb-drug interaction.
E3365	Weigela Grandiflora Fortune Extract	Weigela Grandiflora Fortune Extract is extracted from Weigela Grandiflora Fortune, which decreases the infection-mediated expression of inflammatory mediators by inhibiting the AKT/NF-κB and MAPK signaling pathways.
E4992	Afuresertib hydrochloride	Afuresertib hydrochloride (GSK 2110183 hydrochloride, LAE002 hydrochloride) is an orally bioavailable, selective, ATP-competitive and potent inhibitor of pan-Akt kinase with Ki values of 0.08 nM, 2 nM, 2.6 nM for Akt1/Akt2/Akt3 respectively.
E5820	AKT Kinase Inhibitor	AKT Kinase Inhibitor is an inhibitor of Akt that reverses the protective effects of Tadalafil (TAD) in LPS-induced RWPE-1 cells by decreasing cell viability, promoting apoptosis, and increasing pro-inflammatory cytokine levels.
E7359	A-674563	A-674563 is a selective, orally active inhibitor of Akt1 with a Ki of 11 nM. It also inhibits PKA with Ki of 16 nM and CDK2 with Ki of 46 nM. This compound reduces Akt downstream target phosphorylation and inhibits tumor cell proliferation in vitro with an EC50 of 0.4 µM.
S8500	BAY1125976	BAY 1125976 is a selective allosteric AKT1/2 inhibitor, exhibits high efficacy on AKT signaling-dependent tumor growth in mouse models. This compound inhibits the activity of AKT1 (IC50 = 5.2 nM at 10 µM ATP and 44 nM at 2 mM ATP) and AKT2 (IC50 = 18 nM at 10 µM ATP and 36 nM at 2 mM ATP) very potently. Whereas this chemical is almost inactive on AKT3 (IC50 = 427 nM at 10 µM ATP).
S9611	ABTL-0812	ABTL0812 (α-Hydroxylinoleic acid, LP-10218, SCLN-0812) inhibits Akt/mTOR axis by inducing the overexpression of TRIB3 and activating autophagy in lung squamous carcinoma cell lines. ABTL0812 also induces AMPK activation and ROS accumulation.
E5971New	ZINC00640089	ZINC00640089 is a selective Lipocalin-2 (LCN2) inhibitor that suppresses cell proliferation, decreases cell viability, and reduces AKT phosphorylation levels in SUM149 cells. This compound shows promising research potential for inflammatory breast cancer (IBC) studies.
S3241	Loureirin A	Loureirin A is a flavonoid extracted from the red resin of the herbs of Dracaena cochinchinensis, which is known as Dragon's Blood. This compound inhibits platelet activation by an impairment of PI3K/Akt signaling. It also inhibits Akt phosphorylation.
E1604	Vevorisertib trihydrochloride	Vevorisertib trihydrochloride(ARQ 751 trihydrochloride) is a selective, allosteric inhibitor of pan-AKT and AKT1-E17K mutant with Kd values of 1.2 nM and 8.6 nM, respectively. It also has IC50 values of 0.55, 0.81, and 1.3 nM for AKT1, AKT2, and AKT3, respectively and can be used for the research of cancer.
S2743	PF-04691502	PF-04691502 (PF4691502) is an ATP-competitive PI3K(α/β/δ/γ)/mTOR dual inhibitor with Ki of 1.8 nM/2.1 nM/1.6 nM/1.9 nM and 16 nM in cell-free assays, little activity against either Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK. This compound induces apoptosis. Phase 2.	Cell Death Discov, 2025, 11(1):266 Exp Gerontol, 2024, 186:112359 iScience, 2023, 26(9):107734
S1362	Rigosertib (ON-01910)	Rigosertib (ON-01910) is a non-ATP-competitive inhibitor of PLK1 with IC50 of 9 nM in a cell-free assay, showing 30-fold greater selectivity against Plk2 and no activity to Plk3. It inhibits the PI3K/Akt pathway, activates oxidative stress signals, and induces apoptosis in various cancer cells. This compound is in Phase 3.	Drug Resist Updat, 2025, 81:101251 Drug Resist Updat, 2025, 81:101251 Nat Commun, 2024, 15(1):2089
S2310	Honokiol	Honokiol is the active principle of magnolia extract that inhibits Akt-phosphorylation and promotes ERK1/2 phosphorylation. This compound causes G0/G1 phase arrest, induces apoptosis, and autophagy via the ROS/ERK1/2 signaling pathway. It inhibits hepatitis C virus (HCV) infection. Phase 3.	J Adv Res, 2025, S2090-1232(25)00062-1 J Nanobiotechnology, 2025, 23(1):414 Oncol Lett, 2025, 29(4):191
S3901	Astragaloside IV	Astragaloside IV (AST-IV, AS-IV) is a bioactive saponin first isolated from the dried plant roots of the genus Astragalus, which is used in traditional Chinese medicine. It has various effect on the cardiovascular, immune, digestive, and nervous systems. AS-IV suppresses activation of p-Akt, p-mTOR, p-NF-κB and p-Erk1/2.	Cell Transplant, 2023, 32:9636897231198167 Cell Transplant, 2023, 32:9636897231198167 Cell Cycle, 2022, 1-14
S9190	Oroxin B	Oroxin B (Hypocretin-2), one of flavonoids isolated from traditional Chinese herbal medicine Oroxylum indicum (L.) Vent, selectively induces tumor-suppressive ER stress in malignant lymphoma cells and has antioxidant activity. This compound significantly inhibits proliferation and induce apoptosis, which may be strongly associated with the inhibiting COX-2/VEGF and PTEN/PI3K/AKT signaling pathway in SMMC-7721 cells, it potentially be used as a novel therapeutic agent for liver cancer.COX-2, VEGF, PI3K, and p-AKT expression levels are downregulated, while PTEN is upregulated after this chemical treatment.	Environ Pollut, 2023, 323:121306 Theranostics, 2022, 12(2):910-928 J Cancer, 2021, 12(7):2140-2150
S3238	Resibufogenin	Resibufogenin (Bufogenin, Recibufogenin), a component of huachansu with anticancer effect, triggers necroptosis through upregulating receptor-interacting protein kinase 3 (RIP3) and phosphorylating mixed lineage kinase domain-like protein at Ser358. This compound exerts cytotoxic effect by inducing reactive oxygen species (ROS) accumulation. It induces apoptosis and caspase-3 and caspase-8 activity. This chemical increases Bax/Bcl-2 expression, and suppresses cyclin D1, cyclin E, PI3K, p-AKT, p-GSK3β and β-catenin protein expression.	bioRxiv, 2025, 2025.07.17.665404 Research Square, 2024, 10.21203/rs.3.rs-3790060/v1 Phytomedicine, 2022, 102:154182
S3296	Hispidulin	Hispidulin (Dinatin), an active natrual ingredient in a number of traditional Chinese medicinal herbs, exhibits inhibitory activity against the oncogenic protein kinase Pim-1 with IC50 of 2.71 μM. This compound induces apoptosis through mitochondrial dysfunction and inhibition of P13k/Akt signalling pathway in HepG2 cancer cells. It exerts anti-osteoporotic and bone resorption attenuating effects via activating the AMPK signaling pathway.	Evid Based Complement Alternat Med, 2023, 2023:9428241
E2384	(E)-Akt inhibitor-IV	(E)-Akt inhibitor-IV is a PI3K-Akt inhibitor, with potent cytotoxic.	Res Sq, 2025, rs.3.rs-5931887 Eur J Pharmacol, 2022, 931:175186
S3785	Notoginsenoside R1	Notoginsenoside R1 (Sanchinoside R1) is the main ingredient with cardiovascular activity in Panax notoginseng. It inhibits TNF-α-induced PAI-1 overexpression via extracellular signal-related kinases (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling pathways.	Food Sci Nutr, 2023, 11(12):7791-7802 J Ethnopharmacol, 2021, S0378-8741(21)00169-0
S3810	Scutellarin	Scutellarin (Breviscapine, Breviscapin, Scutellarein-7-glucuronide), the major active principal flavonoids extracted from the Chinese herbal medicines Scutellaria baicalensis and Erigeron breviscapus (Vant.) Hand-Mazz, has many pharmacological effects, such as antioxidant, antitumor, antiviral, and antiinflammatory activities. This compound can down-regulates the STAT3/Girdin/Akt signaling in HCC cells, and inhibits RANKL-mediated MAPK and NF-κB signaling pathway in osteoclasts.	Biomed Pharmacother, 2022, 155:113781
S3220	Trigonelline	Trigonelline (Trigenolline) is a plant alkaloid and a major component of coffee and fenugreek with anti-degranulation, anti-diabetic, antioxidant, anti-inflammatory, and neuroprotective effects. This compound inhibits FcεRI-mediated intracellular signaling pathways, such as phosphorylation of PLCγ1, PI3K, and Akt. It also inhibits the microtubule formation in RBL-2H3 cells.	Int J Med Sci, 2025, 22(5):1194-1207 Biochem Biophys Rep, 2025, 42:102021 Biomed Pharmacother, 2021, 143:112204
S3224	Cinobufagin	Cinobufagin (Cinobufagine), an active ingredient of Venenum Bufonis, inhibits tumor development. This compound increases ATM and Chk2 and decreases CDC25C, CDK1, and cyclin B. It inhibits PI3K, AKT and Bcl-2 while increases levels of cleaved caspase-9 and caspase-3. Thus, this chemical induces cell cycle arrest at the G2/M phase and apoptosis.
S5554	Lanatoside C	Lanatoside C is a cardiac glycoside with antiviral and anti-tumor activity. This compound induces G2/M cell cycle arrest and induces autophagy and apoptosis via attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR signaling pathways.
S3243	Zeaxanthin	Zeaxanthin, the carotenoid alcohol participates in the xanthophyll cycle, activates the extrinsic apoptosis pathway which induces apoptosis on uveal melanoma cells with IC50 value 40.8 µM.
E3656	Dichroa febrifuga Extract	Dichroa Febrifuga Extract is extracted from Dichroa Febrifuga, which can Suppress PI3K/AKT and MAPK Signaling Pathways.
E4864	Pentamidine	Pentamidine (MP-601205) is an aromatic diamidine drug, an antagonist of TLR4.It also inhibits PI3K/AKT signaling pathway and reduce the expression of MMP-2 and MMP-9. It exhibits anti- protozoal, anti-inflammatory, and anti-tumor activities and is used as an agent for treating African trypanosomiasis, antimony resistant leishmaniasis and Pneumocystis carinii pneumonia.
E3106	Dioscoreae Nipponicae Rhizoma Extract	Dioscoreae Nipponicae Rhizoma Extract is extracted from the rhizome of Dioscorea nipponica, of which the main component decreases the phosphorylation in IGF-1R, which in turn inhibits the phosphorylation and activation of PI3K-AKT and Rap1-MEK signaling pathways, promoting cell apoptosis and Graves’ disease remission.
E0020	Lupenone	Lupenone (Lup-20(29)-en-3-one, lupeone) is an isolated compound exhibiting anti-oxidative, anti-inflammation, and anti-diabetic activities. This compound can protect SH-SY5y cells against METH-induced neuronal apoptosis through the PI3K/Akt pathway.
S2298	Fisetin	Fisetin (Fustel) is a potent sirtuin activating compound (STAC) and an agent that modulates sirtuins.	Sci Adv, 2025, 11(17):eads1875 Mol Cancer, 2024, 23(1):222 Cell Death Dis, 2024, 15(8):608
S3309	Solasodine	Solasodine (Purapuridine, Solancarpidine, Solasodin, Salasodine, Salasdine) is a poisonous alkaloid chemical compound that occurs in plants of the Solanaceae family. This compound reduces the mRNA level of matrix metalloproteinase-2 (MMP-2), MMP-9 and extracellular inducer of matrix metalloproteinase (EMMPRIN), but increases the expression of reversion-inducing cysteine-rich protein with kazal motifs (RECK). It downregulates oncogenic microRNA-21 (miR-21), which has been known to target RECK. This chemical also reduces PI3K/Akt signaling pathways and downregulates expression of miR-21.
S9054	Pectolinarin	Pectolinarin is a major compound in Cirsium setidens with anti-inflammatory activity. This compound inhibits secretion of IL-6 and IL-8, as well as the production of PGE2 and NO. It also induces apoptosis via inactivation of the PI3K/Akt pathway.
E0945	BIA	BIA (TMBIM6 antagonist BIA), a potential TMBIM6 antagonist, is an inhibitor of the interaction between TMBIM6 (Transmembrane B cell lymphoma 2-associated X protein (BAX) inhibitor motif-containing 6) and mTORC2, which ultimately blocks AKT activation and cancer progression.
E2682	RPI-1	RPI-1 inhibits proliferation of human papillary thyroid carcinoma cell line TPC-1 by inducing accumulation of cells at the G2 cell cycle phase, abolishes Ret/Ptc1 tyrosine phosphorylation along with its binding to Shc and phospholipase Cg, also abolishes the activation of JNK2 and AKT.
E2826	Hematein	Hematein inhibits casein kinase II activity in a selective, dose-dependent and ATP non-competitive manner in vitro, with IC50 of 0.55 μM in the presence of 10 μM ATP.
E2401	SPP-86	SPP-86, a potent and selective cell permeable inhibitor of rearranged during transfection (RET) tyrosine kinase with an IC50 of 8 nM, inhibits RET-induced phosphatidylinositide 3-kinases (PI3K)/Akt and MAPK signaling, also inhibits RET-induced estrogen receptorα (ERα) phosphorylation in MCF7 cells.
S1321	Urolithin B	Urolithin B inhibits NF-κB activity by reducing the phosphorylation and degradation of IκBα. This compound suppresses the phosphorylation of JNK, ERK, and Akt, and enhances the phosphorylation of AMPK. It is also a regulator of skeletal muscle mass.	PLoS Pathog, 2025, 21(8):e1013401
S1273	Amarogentin	Amarogentin (AG), a secoiridoid glycoside mainly extracted from Swertia and Gentiana roots, exhibits anti-oxidative, anti-tumour, and anti-diabetic activities. This compound is an agonist for the bitter taste receptor TAS2R1 and inhibits in LAD-2 cells substance P-induced production of newly synthesized TNF-α. It induces apoptosis in human gastric cancer cells (SNU-16) through G2/M cell cycle arrest and PI3K/Akt signalling pathway. This chemical interacts with the α2 subunit of AMP-activated protein kinase (AMPK) and activates the trimeric kinase with EC50 of 277 pM.
S7863	SC79	SC79 is a brain-penetrable Akt phosphorylation activator and an inhibitor of Akt-PH domain translocation.	Nat Commun, 2025, 16(1):3734 J Immunother Cancer, 2025, 13(9)e010812 Int J Biol Sci, 2025, 21(5):2118-2134
E2947	Recilisib	Recilisib (ON01210, EX-RAD) is a radioprotectant that activates the activity of AKT and PI3K in cells. It has been studied as prophylactic (use prior to radiation exposure) and therapeutic (after exposure to radiation) drug.
S5144	Neferine	Neferine ((R)-1,2-Dimethoxyaporphine), a natural component of Nelumbo nucifera, has antitumor efficiency. It induces apoptosis in renal cancer cells. This compound prevents autophagy through activation of Akt/mTOR pathway and Nrf2 in muscle cells. It strongly inhibits NF-κB activation. It possesses a number of therapeutic effects such as anti-diabetic, anti-aging, anti-microbial, anti-thrombotic, anti-arrhythmic, anti-inflammatory and even anti-HIV.	J Cosmet Dermatol, 2024, 10.1111/jocd.16587 Bone Res, 2022, 10(1):27 Cell Death Dis, 2022, 13(11):1000
S3294	Demethyl-Coclaurine	Demethyl-Coclaurine (Higenamine, Norcoclaurine), the key component of the Chinese herb aconite root, is a beta-2 adrenergic receptor (β2-AR) agonist. This compound stimulates AKT phosphorylation and requires PI3K activation for the anti-apoptotic effect in cardiomyocytes.	Signal Transduct Target Ther, 2024, 9(1):243
S0765	MAZ51	MAZ51 is a potent and selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-3 (Flt-4) tyrosine kinase. This compound induces cell rounding and G2/M cell cycle arrest in glioma cells through phosphorylation of Akt/GSK3β and activation of RhoA. It inhibits the proliferation and induces the apoptosis of a variety of non-VEGFR-3-expressing tumor cell lines.	Sci Rep, 2025, 15(1):1283
S6760	LM22B-10	LM22B-10 is a small molecule TrkB/TrkC neurotrophin receptor co-activator. This compound selectively activates TrkB, TrkC, AKT and ERK in vivo and in vitro.	Theranostics, 2024, 14(4):1561-1582 Int J Mol Sci, 2024, 25(4)2408 Sci Rep, 2024, 14(1):12090
E0785	YS-49	YS-49 is a PI3K/Akt (a downstream target of RhoA) activator, to reduce RhoA/PTEN activation in the 3-methylcholanthrene-treated cells, inhibits angiotensin II (Ang II)-stimulated proliferation of VSMCs via induction of heme oxygenase (HO)-1, also is an isoquinoline compound alkaloid, has a strong positive inotropic action through activation of cardiac β-adrenoceptors.	Cell Signal, 2025, 131:111752 Signal Transduct Target Ther, 2024, 9(1):243
S9514	Rotundic acid	Rotundic acid (Rutundic acid), a natural compound, exhibit cytotoxic activities toward human hepatocellular carcinoma (HepG2), malignant melanoma (A375), SCLC (NCI-H446), breast cancer (MCF-7), and colon cancer (HT-29) cell lines.RA induces cell cycle arrest, DNA damage, and apoptosis by modulating the AKT/mTOR and MAPK pathways.
S4572	Homosalate	Homosalate (HMS, Homomenthyl salicylate) is an organic ultraviolet filter used in most sunscreens but has been reported to be toxic to marine organisms. This compound aggravates the invasion of human trophoblast cells as well as regulates intracellular signaling pathways including PI3K/AKT and MAPK pathways.
S3289	Daphnoretin	Daphnoretin (Dephnoretin, Thymelol), a biologically active compound isolated from Wikstroemia indica C.A. Mey., is a protein kinase C (PKC) activator. This compound inhibits the proliferation, invasion, and migration of tumor cells and promote its apoptosis by regulating the activity of Akt signal pathway.
S8961	Alobresib (GS-5829)	Alobresib (GS-5829) is a novel BET inhibitor that represents a highly effective therapeutics agent against recurrent/chemotherapy-resistant USC-overexpressing c-Myc. This compound inhibits CLL cell proliferation and induces leukemia cell apoptosis through deregulation of key signaling pathways, such as BLK, AKT, ERK1/2, and MYC. It also inhibits NF-κB signaling.
E2391	α-Linolenic acid	α-Linolenic acid, an essential fatty acid isolated from seed oils, affects the process of thrombotic through the modulation of PI3K/Akt signaling, and possesses the anti-arrhythmic properties.
S6885	Ailanthone	Ailanthone (AIL, Δ13-Dehydrochaparrinone), a natural anti-hepatocellular carcinoma (HCC) component in Ailanthus altissima, induces G0/G1-phase cell cycle arrest by decreasing expression of cyclins and CDKs and increases expression of p21 and p27. This compound triggers DNA damage characterized by activation of the ATM/ATR pathway. It induces apoptosis which is mitochondrion-mediated and involves the PI3K/AKT signaling pathway in Huh7 cells. This chemical is also a potent inhibitor of both full-length Androgen Receptor (AR-FL) and constitutively active truncated AR splice variants (AR-Vs, AR1-651) with IC50 of 69 nM and 309 nM, respectively.	Theranostics, 2024, 14(4):1371-1389
S6982New	3CAI	3CAI inhibits AKT1 and AKT2.
E5971New	ZINC00640089	ZINC00640089 is a selective Lipocalin-2 (LCN2) inhibitor that suppresses cell proliferation, decreases cell viability, and reduces AKT phosphorylation levels in SUM149 cells. This compound shows promising research potential for inflammatory breast cancer (IBC) studies.

Signaling Pathway Map

The PI3K-AKT-MTOR Pathway: A Central Target for AKT Inhibitors

The PI3K-AKT-MTOR pathway is the primary signaling network modulated by AKT inhibitors, serving as a master regulator of cellular homeostasis and malignant transformation. Understanding the architecture and dysregulation of this pathway is fundamental to optimizing the design and application of AKT-targeted therapies.

Pathway Architecture and Physiological Activation

Under physiological conditions, the PI3K-AKT-MTOR pathway is activated by extracellular signals such as growth factors, cytokines, and integrin-mediated cell adhesion. Ligand binding to receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) triggers the recruitment and activation of class I PI3K, which phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3)—a lipid second messenger. PIP3 then recruits AKT and phosphoinositide-dependent kinase 1 (PDK1) to the plasma membrane via their pleckstrin homology (PH) domains. PDK1 phosphorylates AKT at threonine 308 (T308), while mammalian target of rapamycin complex 2 (MTORC2) phosphorylates AKT at serine 473 (S473), leading to full activation of AKT. Activated AKT translocates to the cytoplasm and nucleus, where it phosphorylates a diverse array of downstream substrates, orchestrating processes critical for cell survival (e.g., inhibiting BAD and caspase-9), proliferation (e.g., activating cyclin D1), metabolism (e.g., promoting glucose uptake via GLUT4), and angiogenesis (e.g., upregulating VEGF).

Oncogenic Dysregulation of the PI3K-AKT-MTOR Pathway

In cancer cells, the PI3K-AKT-MTOR pathway is frequently dysregulated through multiple mechanisms, driving uncontrolled cell growth and survival. Common alterations include activating mutations in PIK3CA (encoding the p110α catalytic subunit of PI3K), loss-of-function mutations in PTEN (a phosphatase that dephosphorylates PIP3, antagonizing PI3K signaling), amplifications of AKT1/2/3, and overexpression of RTKs (e.g., EGFR, HER2). These aberrations result in constitutive PIP3 accumulation and AKT activation, independent of extracellular signals. For example, PIK3CA mutations are present in ~30% of breast cancers and ~20% of colorectal cancers, leading to hyperactive PI3K signaling and sustained AKT phosphorylation. Similarly, PTEN loss is prevalent in prostate cancer, glioblastoma, and endometrial cancer, removing a key negative regulator of the pathway. Such dysregulation creates a "addiction" of cancer cells to AKT signaling, making them vulnerable to AKT inhibitors.

AKT Inhibitors: Classification, Protein Targeting, and Kinase Selectivity

AKT inhibitors are classified based on their mechanism of action, with distinct classes differing in their ability to target AKT protein conformations, kinase activity, and upstream/downstream signaling components. Achieving selective targeting of AKT kinases while minimizing off-target effects is a key focus of research, as non-specific inhibition can lead to toxicity and reduced therapeutic efficacy.

Classification of AKT Inhibitors by Mechanism

Three main classes of AKT inhibitors have been developed: ATP-competitive inhibitors, allosteric inhibitors, and PH domain inhibitors. ATP-competitive inhibitors bind to the ATP-binding pocket of AKT, preventing ATP hydrolysis and subsequent kinase activity. These inhibitors typically target the active conformation of AKT and may exhibit cross-reactivity with other kinases (e.g., PDK1, SGK family members) due to structural similarities in ATP-binding domains. Examples include capivasertib (AZD5363) and ipatasertib (GDC-0068), which have advanced to late-stage clinical trials for breast and prostate cancer. Allosteric inhibitors, in contrast, bind to a regulatory pocket outside the ATP-binding site, inducing a conformational change that prevents AKT activation. For instance, MK-2206 binds to the PH domain and adjacent regions, blocking AKT recruitment to the plasma membrane and subsequent phosphorylation by PDK1 and MTORC2. Allosteric inhibitors often exhibit higher selectivity for AKT isoforms, reducing off-target kinase inhibition. PH domain inhibitors, a less developed class, directly target the PH domain of AKT, preventing PIP3 binding and membrane localization—an essential step for AKT activation. While promising, these inhibitors face challenges in achieving sufficient potency and bioavailability.

Protein-Protein Interactions and Kinase Selectivity in Inhibitor Design

A major research focus in AKT inhibitor development is optimizing protein targeting and kinase selectivity. AKT isoforms (AKT1, AKT2, AKT3) share high sequence homology in their kinase domains (~80% identity) but exhibit distinct tissue expression patterns and functional roles: AKT1 is widely expressed and critical for cell survival and proliferation; AKT2 is enriched in insulin-responsive tissues (e.g., liver, muscle) and regulates metabolism and cell motility; AKT3 is predominantly expressed in the brain and plays a role in neuronal development. Non-selective AKT inhibitors may disrupt physiological functions of non-oncogenic isoforms, leading to adverse effects such as hyperglycemia (due to AKT2 inhibition) or neurotoxicity (due to AKT3 inhibition). To address this, researchers have pursued isoform-selective inhibitors by leveraging structural differences in the ATP-binding pocket or allosteric sites of AKT isoforms. For example, AKT1-selective inhibitors exploit a unique amino acid residue in the ATP-binding pocket (e.g., alanine at position 230 in AKT1 vs. serine in AKT2/3), enabling selective binding. Additionally, advances in structural biology—including X-ray crystallography and cryo-electron microscopy—have provided detailed insights into AKT protein conformations, facilitating rational drug design.

Functional Impacts of AKT Inhibitors: From Cellular Responses to Preclinical Efficacy

AKT inhibitors exert profound functional effects on cancer cells by disrupting key oncogenic processes, and preclinical research has been instrumental in defining their mechanisms of action, efficacy, and potential resistance pathways. Understanding these functional impacts is critical for translating AKT inhibitors into effective clinical therapies.

Functional Disruption of Oncogenic Processes

AKT inhibitors induce a range of cellular responses in cancer cells, primarily through inhibiting the phosphorylation of AKT substrates. Key functional effects include: (1) Induction of apoptosis: By inhibiting AKT-mediated phosphorylation of BAD (a pro-apoptotic Bcl-2 family member), AKT inhibitors promote BAD dimerization with Bcl-2/Bcl-XL, releasing Bax/Bak to trigger mitochondrial outer membrane permeabilization and caspase activation. (2) Inhibition of cell proliferation: AKT inhibitors block the phosphorylation of p27Kip1 (a cyclin-dependent kinase inhibitor), leading to p27Kip1 accumulation and cell cycle arrest at the G1 phase. They also downregulate cyclin D1 expression, inhibiting progression through the G1-S checkpoint. (3) Suppression of metabolism: AKT inhibitors reduce glucose uptake and glycolysis by inhibiting the translocation of GLUT4 to the plasma membrane and downregulating hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2)—key enzymes in the Warburg effect. (4) Inhibition of angiogenesis: By downregulating VEGF and HIF-1α (hypoxia-inducible factor 1α), AKT inhibitors reduce tumor vascularization, limiting nutrient and oxygen supply to malignant cells. These functional effects are not mutually exclusive; for example, metabolic suppression can enhance apoptotic sensitivity, creating a synergistic anti-tumor response.

Preclinical Efficacy and Combination Therapy Strategies

Preclinical studies using cancer cell lines, patient-derived xenografts (PDXs), and genetically engineered mouse models (GEMMs) have demonstrated the efficacy of AKT inhibitors in multiple cancer types. For instance, capivasertib has shown potent anti-tumor activity in PDX models of triple-negative breast cancer (TNBC) and castration-resistant prostate cancer (CRPC), particularly in tumors with PI3K-AKT pathway alterations. However, monotherapy with AKT inhibitors often leads to the development of resistance, limiting long-term efficacy. Common resistance mechanisms include: (1) Upregulation of alternative survival pathways (e.g., MAPK/ERK, STAT3); (2) Amplification or activation of RTKs (e.g., EGFR, FGFR) that reactivate PI3K-AKT signaling; (3) Mutations in AKT that reduce inhibitor binding (e.g., E17K mutation in AKT1); (4) Activation of MTORC1 via alternative routes (e.g., amino acid signaling). To overcome resistance, researchers have explored combination therapy strategies, such as combining AKT inhibitors with PI3K inhibitors, MTOR inhibitors, RTK inhibitors, or immune checkpoint inhibitors. For example, the combination of capivasertib (AKT inhibitor) and taselisib (PI3K inhibitor) has shown synergistic anti-tumor activity in PIK3CA-mutant breast cancer models, as dual inhibition of PI3K and AKT prevents reactivation of the pathway. Similarly, combining AKT inhibitors with anti-PD-1/PD-L1 antibodies enhances anti-tumor immunity by reducing the expression of immunosuppressive molecules (e.g., PD-L1) on cancer cells and promoting T cell infiltration.

Crosstalk Between AKT Inhibitors and PI3K/MTOR Signaling: Implications for Research and Therapy

The PI3K-AKT-MTOR pathway is characterized by extensive crosstalk and feedback loops, and AKT inhibitors modulate this network in complex ways that impact their therapeutic efficacy. Research into this crosstalk has uncovered critical insights into pathway regulation and identified novel therapeutic opportunities.

PI3K-AKT-MTOR Crosstalk and Feedback Activation

AKT inhibition can trigger feedback activation of upstream components of the PI3K-AKT-MTOR pathway, limiting inhibitor efficacy. For example, AKT phosphorylates and inhibits RTKs (e.g., EGFR) via a negative feedback loop; blocking AKT activity relieves this inhibition, leading to RTK phosphorylation and increased PI3K activation. Similarly, AKT inhibits the adapter protein IRS-1; AKT inhibition enhances IRS-1 stability and PI3K recruitment. Feedback activation can also occur downstream of AKT: AKT phosphorylates and inhibits TSC2 (a negative regulator of MTORC1), so AKT inhibition leads to TSC2 dephosphorylation and reduced MTORC1 activity. However, prolonged MTORC1 inhibition can activate RTK-PI3K signaling via another feedback loop, reactivating AKT. These feedback mechanisms highlight the need for combinatorial targeting of PI3K, AKT, and MTOR to disrupt the pathway comprehensively.

Therapeutic Implications of PI3K/MTOR Co-Targeting

Preclinical and clinical studies have demonstrated that co-targeting PI3K, AKT, and MTOR can overcome feedback activation and improve therapeutic outcomes. For example, combining the PI3K inhibitor alpelisib with the AKT inhibitor capivasertib has shown promising efficacy in PIK3CA-mutant breast cancer, as alpelisib blocks upstream PI3K activation, while capivasertib inhibits AKT, preventing feedback-driven RTK activation. Similarly, combining AKT inhibitors with MTOR inhibitors (e.g., everolimus) targets both AKT and its downstream effector MTORC1, disrupting the pathway at multiple nodes. However, co-targeting can increase toxicity (e.g., hyperglycemia, diarrhea, myelosuppression), so optimizing dosing schedules and patient selection is critical. Biomarker research is also ongoing to identify patients most likely to benefit from PI3K/AKT/MTOR co-targeting, such as those with PIK3CA mutations, PTEN loss, or high AKT phosphorylation levels.