Bcl-2

Apoptosis

Isoform-selective Products

• All (60)
• Bcl-2 Inhibitors (41)
• Bcl-2 Activators (7)
• Bcl-2 Antagonists (5)
• Bcl-2 Modulators (5)
• New Bcl-2 Products

Cat.No.	Product Name	Information	Product Use Citations	Product Validations
S8048	Venetoclax (ABT-199)	Venetoclax (ABT-199, GDC-0199) is a Bcl-2-selective inhibitor with Ki of <0.01 nM in cell-free assays, >4800-fold more selective versus Bcl-xL and Bcl-w, and no activity to Mcl-1. This compound is reported to induce cell growth suppression, apoptosis, cell cycle arrest, and autophagy in triple negative breast cancer MDA-MB-231 cells. Phase 3.	Cell, 2025, S0092-8674(25)00689-0 Cell, 2025, S0092-8674(25)01233-4 Signal Transduct Target Ther, 2025, 10(1):161
S1002	ABT-737	ABT-737 is a BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w with EC50 of 78.7 nM, 30.3 nM and 197.8 nM in cell-free assays, respectively; no inhibition observed against Mcl-1, Bcl-B or Bfl-1. ABT-737 induces mitochondrial pathway apoptosis and mitophagy. Phase 2.	Signal Transduct Target Ther, 2025, 10(1):161 J Hepatol, 2025, S0168-8278(24)02830-7 Cell Rep Med, 2025, S2666-3791(25)00057-6
S1001	Navitoclax (ABT-263)	A potent inhibitor of Bcl-xL, Bcl-2 and Bcl-w with Ki of ≤ 0.5 nM, ≤1 nM and ≤1 nM in cell-free assays, Navitoclax (ABT-263) binds more weakly to Mcl-1 and A1. Phase 2.	Cell, 2025, S0092-8674(25)00689-0 Nat Cancer, 2025, 6(2):259-277 Nat Metab, 2025, 7(12):2474-2488.
S1057	Obatoclax Mesylate (GX15-070)	Obatoclax Mesylate (GX15-070) is an antagonist of Bcl-2 with Ki of 0.22 μM in a cell-free assay, can assist in overcoming MCL-1 mediated resistance to apoptosis.	Nat Commun, 2025, 16(1):2416 bioRxiv, 2024, 10.1101/2023.01.18.524628 Emerg Microbes Infect, 2022, 1-29
S8383	S63845	S63845 is a new, selective MCL-1 inhibitor with the Kd value of 0.19 nM and has no discernible binding to the other BCL-2 members, BCL-2 or BCL-XL.	Mol Cancer, 2025, 24(1):154 Nat Commun, 2025, 16(1):7853 Nat Commun, 2025, 16(1):4563
S7790	A-1210477	A-1210477 is a potent and selective MCL-1 inhibitor with Ki and IC50 of 0.454 nM and 26.2 nM, respectively, >100-fold selectivity over other Bcl-2 family members.	Front Pharmacol, 2025, 16:1530270 Front Pharmacol, 2025, 16:1530270 Cell Rep, 2023, 42(10):113176
S1121	TW-37	TW-37 is a novel nonpeptide inhibitor to recombinant Bcl-2, Bcl-xL and Mcl-1 with Ki of 0.29 μM, 1.11 μM and 0.26 μM in cell-free assays, respectively.	Signal Transduct Target Ther, 2025, 10(1):161 bioRxiv, 2024, 10.1101/2023.01.18.524628 Cells, 2023, 12(18)2247
S7801	A-1331852	A-1331852 is a potent and selectiveBCL-XL inhibitor with Ki value less than 0.01 nM for BCL-XL and 6 nM, 4 nM, 142 nM for Bcl-2, Bcl-W, MCL-1 respectively. It may be useful in the treatment of cancer, immune and autoimmune diseases.	Cell, 2025, S0092-8674(25)00689-0 Mol Cancer, 2025, 24(1):154 Haematologica, 2025, 110(1):78-91
S7800	A-1155463 Dihydrochloride	A-1155463 Dihydrochloride, a highly potent and selective BCL-XL inhibitor, shows picomolar binding affinity to BCL-XL, and >1000-fold weaker binding to BCL-2 and related proteins BCL-W(Ki=19 nM) and MCL-1(Ki>440 nM).	Front Pharmacol, 2025, 16:1530270 Front Pharmacol, 2025, 16:1530270 iScience, 2024, 27(1):108503
S7531	UMI-77	UMI-77 is a selective Mcl-1 inhibitor with Ki of 490 nM, showing selectivity over other members of Bcl-2 family.	iScience, 2024, 27(1):108503 Blood, 2022, blood.2021014304 Nat Commun, 2022, 13(1):6226
S2812	(R)-(-)-Gossypol (AT-101) acetic acid	(R)-(-)-Gossypol (AT-101) acetic acid, the R-(-) enantiomer of Gossypol acetic acid, binds with Bcl-2, Bcl-xL and Mcl-1 with Ki of 0.32 μM, 0.48 μM and 0.18 μM in cell-free assays; does not inhibit BIR3 domain and BID. AT-101 simultaneously triggers apoptosis and a cytoprotective type of autophagy. Phase 2.	Protein Cell, 2024, pwad065 Int J Mol Sci, 2023, 24(7)6662 Leiden University The Netherlands, 2023,
S8643	AZD5991	AZD5991 is a macrocyclic MCL-1 inhibitor with sub-nanomolar affinity for MCL-1 (Ki = 0.13 nM). The binding affinity of this compound is about 25-fold lower for mouse Mcl-1 vs. human Mcl-1 but only four-fold lower for rat Mcl-1.	Theranostics, 2025, 15(7):2834-2851 Theranostics, 2025, 15(12):5705-5718 Cell Death Differ, 2025, 10.1038/s41418-025-01514-7
S8061	Sabutoclax	Sabutoclax (BI-97C1) is a pan-Bcl-2 inhibitor, including Bcl-xL, Bcl-2, Mcl-1 and Bfl-1 with IC50 of 0.31 μM, 0.32 μM, 0.20 μM and 0.62 μM, respectively.	Cells, 2023, 12(18)2247 Cells, 2023, 10.3390/cells12182247 Mol Divers, 2022, 10.1007/s11030-022-10494-6
S7100	WEHI-539	WEHI-539 has high affinity (IC50=1.1 nM) and selectivity for BCL-XL and potently kills cells by selectively antagonizing its prosurvival activity. This compound has more than a 400-fold higher affinity for BCL-XL versus other prosurvival BCL-2 family members.	bioRxiv, 2025, 2025.06.10.658786 Cell Rep Med, 2023, 4(11):101290 Leiden University The Netherlands, 2023,
S1071	HA14-1	HA14-1 is a non-peptidic ligand of a Bcl-2 surface pocket with IC50 of ~9 μM.	Cell Rep, 2025, 44(5):115617 Platelets, 2020, 10.1080/09537104.2020.1724276 Oncotarget, 2018, 9(24):16701-16717
S8836	MIK665 (S64315)	MIK665 (S64315) is an inhibitor of induced myeloid leukemia cell differentiation protein Mcl-1 with Ki value of 1.2 nM and has potential pro-apoptotic and antineoplastic activities.	Biochem Biophys Res Commun, 2025, 784:152650 Nat Commun, 2024, 15(1):1581 Cancer Biol Ther, 2024, 25(1):2427374
S6709	Obatoclax (GX15-070)	Obatoclax (GX15-070) is an antagonist of Bcl-2 with an Ki of 0.22 μM in a cell-free assay, can assist in overcoming MCL-1 mediated resistance to apoptosis.	Signal Transduct Target Ther, 2025, 10(1):161 Oncotarget, 2024, 15:614-633 Cells, 2023, 12(18)2247
S2448	Gambogic Acid	Gambogic Acid (Guttatic Acid, Guttic Acid, Beta-Guttiferrin) activates caspases with EC50 of 0.78-1.64 μM and competitively inhibits Bcl-XL, Bcl-2, Bcl-W, Bcl-B, Bfl-1 and Mcl-1 with IC50 of 1.47, 1.21, 2.02, 0.66, 1.06 and 0.79 μM, respectively.	Theranostics, 2025, 15(11):5420-5439 Cells, 2023, 12(18)2247 Cells, 2023, 10.3390/cells12182247
S7126	Marinopyrrole A (Maritoclax)	Maritoclax (Marinopyrrole A) is a selective Mcl-1 antagonist that binds to Mcl-1, but not Bcl-XL, and targets it for proteasomal degradation. This compound disrupts the interaction between Bim and Mcl-1 with an IC50 of 10.1 μM.	Clin Cancer Res, 2023, 29(2):446-457 Clin Cancer Res, 2023, 29(2):446-457 Cell Signal, 2022, S0898-6568(22)00041-9
S8865	BAI1	BAI1 is a direct allosteric inhibitor of BAX with a dissociation constant (Kd) of 15.0 ± 4 μM.	Biomed Pharmacother, 2025, 187:118049 Int J Hyperthermia, 2024, 41(1):2325489 Nat Commun, 2023, 14(1):865
E2926	A-1155463	A-1155463 is a highly potent and selective BCL-XL inhibitor with EC50 of 65 nM in H146 cells.	Nat Commun, 2025, 16(1):256 Cell Rep Med, 2025, 6(6):102160 Theranostics, 2025, 15(12):5705-5718
S8650	BTSA1	BTSA1 is a pharmacologically optimized BAX activator that binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis. It effectively promotes apoptosis in leukemia cell lines and patient samples while sparing healthy cells.	bioRxiv, 2024, 10.1101/2023.01.18.524628 Cell Mol Life Sci, 2023, 80(10):311 Cell Mol Life Sci, 2023, 80(10):311
S8759	S55746	S55746 (S 055746,BCL201) is a novel, orally active BCL-2 specific inhibitor (Ki = 1.3 nM) with poor affinity for BCL-XL and no significant binding to MCL-1, BFL-1 (BCL2A1/A1). The selectivity of this compound for BCL-2 versus BCL-XL ranges from ~70 to 400 folds.	Cells, 2023, 12(18)2247 Cells, 2023, 10.3390/cells12182247 Signal Transduct Target Ther, 2022, 7(1):51
S7105	BAM7	BAM 7 is a direct and selective activator of proapoptotic Bax with EC50 of 3.3 μM.	Nat Chem Biol, 2019, 15(4):322-330 Cell Death Discov, 2018, 4:107 Baltimore, Maryland , 2018,
S8199	Ruxotemitide (LTX 315)	Ruxotemitide (LTX 315) is the oncolytic peptide that kills cancer cells through Bax/Bak-regulated mitochondrial membrane permeabilization.	J Immunother Cancer, 2022, 10(3)e004129 Nat Metab, 2021, 10.1038/s42255-021-00491-8
S7849	BDA-366	BDA-366 is a small-molecule Bcl2-BH4 domain antagonist and binds BH4 with high affinity and selectivity. It directly binds to Bcl2 with high binding affinity (Ki =3.3 ± 0.73 nM).	Biochem Pharmacol, 2025, S0006-2952(25)00712-9 BMC Cancer, 2023, 23(1):479
S0563	10-Deacetyl-7-xylosyl paclitaxel	10-Deacetyl-7-xylosyl paclitaxel (10-Deacetyl-7-xylosyltaxol, 7-xylosyl-10-deacetylpaclitaxel), a derivative of paclitaxel and naturally occurring xyloside isolated from Taxus chinensis, causes significant mitotic arrest in PC-3 cells followed by up-regulating expression of pro-apoptotic Bax and Bad protein, as well as down-regulating expression of anti-apoptotic Bcl-2 and Bcl-XL , which leads to a disturbance of the mitochondrial membrane permeability and to the activation of caspase-9.	Cell Death Dis, 2022, 13-9:799
E3037	Solanum lyratum Extract	Solanum lyratum Extract (300 μg/ml) increases Bax levels and decreases Bcl-2 levels, which cause the loss of mitochondrial membrane potential (Δæm) followed by cytochrome C release and caspase-9 and -3 activation, finally leading to apoptosis. This compound also promotes p53 and p27, but decreases the levels of cyclin B1 thus causing S-phase arrest.
S9970	APG-2575 (lisaftoclax)	APG-2575 (lisaftoclax) is a dual Bcl-2 and Bcl-xl inhibitor with IC50 values of 2 nM and 5.9 nM for Bcl-2 and Bcl-xl, respectively.
E8278New	WH244	WH244 is a second-generation PROTAC that selectively degrades the anti-apoptotic proteins BCL-xL and BCL-2 with a DC50 of 0.6 nM for BCL-xL and 7.4 nM for BCL-2.
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.
E0011	Linderalactone	Linderalactone inhibits human lung cancer growth by modulating the expression of apoptosis-related proteins (Bax and Bcl-2) with an IC50 of 15 µM in A-549 cells. This compound induces G2/M cell cycle arrest and could also suppress the JAK/STAT signalling pathway. It can be isolated from Radix linderae.
S9276	Alisol B	Alisol B, a triterpene from Alismatis rhizoma, induces Bax up-regulation and nuclear translocation, the activation of initiator caspase-8 and caspase-9, and executor caspase-3, suggesting the involvement of both extrinsic and intrinsic apoptosis pathways.
E1510	Sonrotoclax	Sonrotoclax(BGB-11417) is a highly potent, orally active and selective inhibitor of Bcl2. This compound demonstrates increased potency along with in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant. Bcl-xL It has effective cell killing effect against a variety of lymphoma and leukemia cell lines.
S5600	Flavokawain A	Flavokawain A, extracted from kava, is an apoptotic inducers and anticarcinogenic agent. This compound can down-regulation of antiapoptotic proteins, such as XIAP, survivin, and Bcl-xL, thereby changing the balance between apoptotic and antiapoptotic molecules and then induce cell death in tumor cells.
S8177	BH3I-1	BH3I-1 is a Bcl-XL-BH3 domain interaction inhibitor with Ki of 2.4 μM (by fluorescence polarization ).This compound is a selective inhibitor of Bcl-2 family proteins.
S8924	DT2216	DT2216 is a potent and selective degrader of BCL-XL based on PROTAC technology. DT2216 inhibits various BCL-XL-dependent leukemia and cancer cells but considerably less toxic to platelets.
S6004	CCI-007	CCI-007 is a novel small molecule with cytotoxic activity against infant leukemia with MLL rearrangements.
S8758	VU661013	VU661013 is a novel, potent, selective MCL1 inhibitor with Ki of 97 ± 30 pM of human MCL-1 in a TR-FRET assay. However, this compound does not significantly inhibit BCL-xL or BCL-2 with Ki > 40 μM or = 0.73 μM. It de-stabilizes BIM/MCL-1 association, leads to apoptosis in AML.	Gastric Cancer, 2025, 10.1007/s10120-025-01630-w
S8550	Tapotoclax (AMG-176)	Tapotoclax (AMG-176) is a potent, selective, and orally bioavailable macrocyclic inhibitor of MCL1 with a Ki of 0.13 nM. It induces a potent apoptosis in models of hematologic malignancies.
E2663	BT2	BT2 is a novel branched-chain α-ketoacid dehydrogenase complex kinase (BDK) inhibitor wieh an IC50 of 3.19 μM.
E5962New	BRD-810	BRD-810 is a potent and highly selective inhibitor of MCL1. BRD-810 targets the BH3-binding pocket of MCL1 and blocks the capturing of pro-apoptotic proteins, thereby rapidly triggering caspase activation in MCL1-dependent cells. It demonstrates potent anti-tumor effects in both hematologic malignancies and solid tumor models.
E3020	Hedyotic Diffusa Extract	Hedyotic Diffusa Extract is extracted from Hedyotic diffusa, of which polysaccharides inhibit the growth of CNE2 cells in a dose-and-time-dependent way, the mechanism may involve induction of cell apoptosis, which is associated with the activation of Bax and caspase-3 protein and the down-regulation of Bcl-2 protein expression.
S7747	Ro-3306	RO-3306 is an ATP-competitive, and selective CDK1 inhibitor with Ki of 20 nM, >15-fold selectivity against a diverse panel of human kinases. RO-3306 enhances p53-mediated Bax activation and mitochondrial apoptosis.	Nat Commun, 2025, 16(1):7898 Nat Commun, 2025, 16(1):6439 Nucleic Acids Res, 2025, 53(21)gkaf1179
S2606	Mifepristone (RU486)	Mifepristone is a remarkably active antagonist of progesterone receptor and glucocorticoid receptor with IC50 of 0.2 nM and 2.6 nM, respectively. Mifepristone promotes cell autophagy and apoptosis, decreases Bcl-2 level and increases Beclin1 level, accompanied by weakened interaction between Bcl-2 and Beclin1.Mifepristone (RU486) can be used to induce animal models of Spontaneous Abortion.	Pharmacol Res, 2025, 215:107696 Cell Death Dis, 2025, 16(1):237 J Virol, 2025, 99(2):e0147224
S8820	Unesbulin (PTC596)	Unesbulin (PTC596) is a second-generation BMI-1 inhibitor that accelerates BMI-1 degradation. This compound downregulates MCL-1 and induces p53-independent mitochondrial apoptosis. IC50 values at 72 hours ranged from 68 to 340 nM in mantle cell lymphoma (MCL) cell lines.	Cell Rep Med, 2025, S2666-3791(25)00150-8 NPJ Precis Oncol, 2024, 8(1):68 PLoS One, 2023, 18(2):e0277313
S6852	Gossypol	Gossypol (BL 193) is an orally-active polyphenol isolated from cotton seeds and roots. This compound is a potent inhibitor of 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase with IC50 of 3.33 μM and 0.52 μM in cell-free assay, respectively. It also inhibits the binding of BH3 peptide to Bcl protein with IC50 of 0.4 μM and 10 μM for Bcl-XL and Bcl-2, respectively. This chemical induces apoptosis and cell growth inhibition in various cancer cells.	iScience, 2024, 27(10):110862 Cells, 2023, 12(18)2247 Cells, 2023, 10.3390/cells12182247
S3275	Senkyunolide I	Senkyunolide I (SEI, SENI) is an orally active compound isolated from Ligusticum chuanxiong with analgesic, anti-migraine, neuroprotective, anti-oxidation and anti-apoptosis activities. This compound up-regulates the phosphorylation of Erk1/2 and induces Nrf2 nuclear translocation with enhanced HO-1 and NQO1 expressions. It also promotes the ratio of Bcl-2/Bax and inhibits the expressions of cleaved caspase 3 and caspase 9.	Blood Sci, 2025, 7(3):e00246 iScience, 2024, 27(7):110367 World J Emerg Med, 2024, 15(3):206-213
S5967	Berberine chloride hydrate	Berberine (Natural Yellow 18) chloride hydrate is a quaternary ammonium salt from the group of isoquinoline alkaloids. Berberine activates caspase 3 and caspase 8, cleavage of poly ADP-ribose polymerase (PARP) and the release of cytochrome c. Berberine chloride decreases the expression of c-IAP1, Bcl-2 and Bcl-XL. Berberine chloride induces apoptosis with sustained phosphorylation of JNK and p38 MAPK, as well as generation of the ROS. Berberine chloride is a dual topoisomerase I and II inhibitor. Berberine chloride is also a potential autophagy modulator.	Front Biosci (Landmark Ed), 2022, 27(8):242 Front Pharmacol, 2021, 12:632201
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
E0124	Chelerythrine	Chelerythrine (Toddaline, Broussonpapyrine) is a potent, selective antagonist of PKC with an IC50 of 0.66 μM. This compound also inhibits the BclXL-Bak BH3 peptide binding with an IC50 of 1.5 μM. It shows antitumor, antidiabetic and anti-inflammatory activity.	Nutr Neurosci, 2022, 1-19
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.
S6895	TCPOBOP	TCPOBOP is a constitutive androstane receptor (CAR) agonist. This compound attenuates Fas-induced murine liver injury by altering Bcl-2 proteins.
S3245	Nodakenetin	Nodakenetin (NANI), a plant-derived coumarin isolated from Angelica decursiva, inhibits α-glucosidase, PTP1B, rat lens aldose reductase (RLAR), AChE, BChE, and β-site amyloid precursor protein cleaving enzyme 1 (BACE1). This compound alters the protein expression of Bax and Bcl-2, and prompts mitochondrial apoptosis. It exhibits anti-tumor activity.
S3267	Nicotiflorin (Kaempferol-3-O-rutinoside)	Nicotiflorin (Kaempferol-3-O-rutinoside), a flavonoid extracted from Carthamus tinctorius, alters the shape and structure of injured neurons, decreases the number of apoptotic cells, down-regulates expression of p-JAK2, p-STAT3, caspase-3, and Bax and decreases Bax immunoredactivity, and increases Bcl-2 protein expression and immunoreactivity.
E2354	Valepotriate	Valepotriate, an unstable iridoid isolated from Valeriana jatamansi Jones, has anti-epileptic by significantly increasing the expression of GABAA, glutamic acid decarboxylase 65, and Bcl-2 and reduce the expression of caspase-3.
E2028	Humanin	Humanin (human) (1-24-Protein humanin (human)), a small mitochondrial-derived cytoprotective polypeptide encoded by mtDNA, exhibits protective effects in several cell types against cellular stress conditions and apoptosis through regulating various signaling mechanisms, such as JAK/STAT pathway and interaction of BCL-2 family of protein.
S2271	Berberine chloride	Berberine chloride is a quaternary ammonium salt from the group of isoquinoline alkaloids. This compound activates caspase 3 and caspase 8, cleavage of poly ADP-ribose polymerase (PARP) and the release of cytochrome c. It decreases the expression of c-IAP1, Bcl-2 and Bcl-XL. This chemical induces apoptosis with sustained phosphorylation of JNK and p38 MAPK, as well as generation of the ROS. It is a dual topoisomerase I and II inhibitor. It is also a potential autophagy modulator.	J Cardiovasc Dev Dis, 2025, 12(7)278 Adv Healthc Mater, 2023, e2300591. Transl Oncol, 2023, 35:101712
S9665	Motixafortide (BKT140)	Motixafortide (BL-8040, BKT140, TF 14016, 4-fluorobenzoyl, 4F-benzoyl-TN14003, T140) is an antagonist of CXCR4 with IC50 of ～1 nM. BL-8040 induces the apoptosis of AML blasts by down-regulating ERK, BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression.	King's College London, 2023,
S5550	Ethyl gallate	Ethyl gallat (Phyllemblin, gallic acid ethyl ester), which could be found naturally in a variety of plant sources, is a food additive with antimicrobial activity. Ethyl gallat activates the death receptor-dependent pathway of apoptosis by enhancing the expression of caspases-8, -9, and -3 and the Bcl-2 interacting domain (Bid).	Front Pharmacol, 2024, 15:1403424
S8048	Venetoclax (ABT-199)	Venetoclax (ABT-199, GDC-0199) is a Bcl-2-selective inhibitor with Ki of <0.01 nM in cell-free assays, >4800-fold more selective versus Bcl-xL and Bcl-w, and no activity to Mcl-1. This compound is reported to induce cell growth suppression, apoptosis, cell cycle arrest, and autophagy in triple negative breast cancer MDA-MB-231 cells. Phase 3.	Cell, 2025, S0092-8674(25)00689-0 Cell, 2025, S0092-8674(25)01233-4 Signal Transduct Target Ther, 2025, 10(1):161
S1002	ABT-737	ABT-737 is a BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w with EC50 of 78.7 nM, 30.3 nM and 197.8 nM in cell-free assays, respectively; no inhibition observed against Mcl-1, Bcl-B or Bfl-1. ABT-737 induces mitochondrial pathway apoptosis and mitophagy. Phase 2.	Signal Transduct Target Ther, 2025, 10(1):161 J Hepatol, 2025, S0168-8278(24)02830-7 Cell Rep Med, 2025, S2666-3791(25)00057-6
S1001	Navitoclax (ABT-263)	A potent inhibitor of Bcl-xL, Bcl-2 and Bcl-w with Ki of ≤ 0.5 nM, ≤1 nM and ≤1 nM in cell-free assays, Navitoclax (ABT-263) binds more weakly to Mcl-1 and A1. Phase 2.	Cell, 2025, S0092-8674(25)00689-0 Nat Cancer, 2025, 6(2):259-277 Nat Metab, 2025, 7(12):2474-2488.
S8383	S63845	S63845 is a new, selective MCL-1 inhibitor with the Kd value of 0.19 nM and has no discernible binding to the other BCL-2 members, BCL-2 or BCL-XL.	Mol Cancer, 2025, 24(1):154 Nat Commun, 2025, 16(1):7853 Nat Commun, 2025, 16(1):4563
S7790	A-1210477	A-1210477 is a potent and selective MCL-1 inhibitor with Ki and IC50 of 0.454 nM and 26.2 nM, respectively, >100-fold selectivity over other Bcl-2 family members.	Front Pharmacol, 2025, 16:1530270 Front Pharmacol, 2025, 16:1530270 Cell Rep, 2023, 42(10):113176
S1121	TW-37	TW-37 is a novel nonpeptide inhibitor to recombinant Bcl-2, Bcl-xL and Mcl-1 with Ki of 0.29 μM, 1.11 μM and 0.26 μM in cell-free assays, respectively.	Signal Transduct Target Ther, 2025, 10(1):161 bioRxiv, 2024, 10.1101/2023.01.18.524628 Cells, 2023, 12(18)2247
S7801	A-1331852	A-1331852 is a potent and selectiveBCL-XL inhibitor with Ki value less than 0.01 nM for BCL-XL and 6 nM, 4 nM, 142 nM for Bcl-2, Bcl-W, MCL-1 respectively. It may be useful in the treatment of cancer, immune and autoimmune diseases.	Cell, 2025, S0092-8674(25)00689-0 Mol Cancer, 2025, 24(1):154 Haematologica, 2025, 110(1):78-91
S7800	A-1155463 Dihydrochloride	A-1155463 Dihydrochloride, a highly potent and selective BCL-XL inhibitor, shows picomolar binding affinity to BCL-XL, and >1000-fold weaker binding to BCL-2 and related proteins BCL-W(Ki=19 nM) and MCL-1(Ki>440 nM).	Front Pharmacol, 2025, 16:1530270 Front Pharmacol, 2025, 16:1530270 iScience, 2024, 27(1):108503
S7531	UMI-77	UMI-77 is a selective Mcl-1 inhibitor with Ki of 490 nM, showing selectivity over other members of Bcl-2 family.	iScience, 2024, 27(1):108503 Blood, 2022, blood.2021014304 Nat Commun, 2022, 13(1):6226
S2812	(R)-(-)-Gossypol (AT-101) acetic acid	(R)-(-)-Gossypol (AT-101) acetic acid, the R-(-) enantiomer of Gossypol acetic acid, binds with Bcl-2, Bcl-xL and Mcl-1 with Ki of 0.32 μM, 0.48 μM and 0.18 μM in cell-free assays; does not inhibit BIR3 domain and BID. AT-101 simultaneously triggers apoptosis and a cytoprotective type of autophagy. Phase 2.	Protein Cell, 2024, pwad065 Int J Mol Sci, 2023, 24(7)6662 Leiden University The Netherlands, 2023,
S8643	AZD5991	AZD5991 is a macrocyclic MCL-1 inhibitor with sub-nanomolar affinity for MCL-1 (Ki = 0.13 nM). The binding affinity of this compound is about 25-fold lower for mouse Mcl-1 vs. human Mcl-1 but only four-fold lower for rat Mcl-1.	Theranostics, 2025, 15(7):2834-2851 Theranostics, 2025, 15(12):5705-5718 Cell Death Differ, 2025, 10.1038/s41418-025-01514-7
S8061	Sabutoclax	Sabutoclax (BI-97C1) is a pan-Bcl-2 inhibitor, including Bcl-xL, Bcl-2, Mcl-1 and Bfl-1 with IC50 of 0.31 μM, 0.32 μM, 0.20 μM and 0.62 μM, respectively.	Cells, 2023, 12(18)2247 Cells, 2023, 10.3390/cells12182247 Mol Divers, 2022, 10.1007/s11030-022-10494-6
S1071	HA14-1	HA14-1 is a non-peptidic ligand of a Bcl-2 surface pocket with IC50 of ~9 μM.	Cell Rep, 2025, 44(5):115617 Platelets, 2020, 10.1080/09537104.2020.1724276 Oncotarget, 2018, 9(24):16701-16717
S8836	MIK665 (S64315)	MIK665 (S64315) is an inhibitor of induced myeloid leukemia cell differentiation protein Mcl-1 with Ki value of 1.2 nM and has potential pro-apoptotic and antineoplastic activities.	Biochem Biophys Res Commun, 2025, 784:152650 Nat Commun, 2024, 15(1):1581 Cancer Biol Ther, 2024, 25(1):2427374
S2448	Gambogic Acid	Gambogic Acid (Guttatic Acid, Guttic Acid, Beta-Guttiferrin) activates caspases with EC50 of 0.78-1.64 μM and competitively inhibits Bcl-XL, Bcl-2, Bcl-W, Bcl-B, Bfl-1 and Mcl-1 with IC50 of 1.47, 1.21, 2.02, 0.66, 1.06 and 0.79 μM, respectively.	Theranostics, 2025, 15(11):5420-5439 Cells, 2023, 12(18)2247 Cells, 2023, 10.3390/cells12182247
S8865	BAI1	BAI1 is a direct allosteric inhibitor of BAX with a dissociation constant (Kd) of 15.0 ± 4 μM.	Biomed Pharmacother, 2025, 187:118049 Int J Hyperthermia, 2024, 41(1):2325489 Nat Commun, 2023, 14(1):865
E2926	A-1155463	A-1155463 is a highly potent and selective BCL-XL inhibitor with EC50 of 65 nM in H146 cells.	Nat Commun, 2025, 16(1):256 Cell Rep Med, 2025, 6(6):102160 Theranostics, 2025, 15(12):5705-5718
S8759	S55746	S55746 (S 055746,BCL201) is a novel, orally active BCL-2 specific inhibitor (Ki = 1.3 nM) with poor affinity for BCL-XL and no significant binding to MCL-1, BFL-1 (BCL2A1/A1). The selectivity of this compound for BCL-2 versus BCL-XL ranges from ~70 to 400 folds.	Cells, 2023, 12(18)2247 Cells, 2023, 10.3390/cells12182247 Signal Transduct Target Ther, 2022, 7(1):51
S9970	APG-2575 (lisaftoclax)	APG-2575 (lisaftoclax) is a dual Bcl-2 and Bcl-xl inhibitor with IC50 values of 2 nM and 5.9 nM for Bcl-2 and Bcl-xl, respectively.
E8278New	WH244	WH244 is a second-generation PROTAC that selectively degrades the anti-apoptotic proteins BCL-xL and BCL-2 with a DC50 of 0.6 nM for BCL-xL and 7.4 nM for BCL-2.
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.
E0011	Linderalactone	Linderalactone inhibits human lung cancer growth by modulating the expression of apoptosis-related proteins (Bax and Bcl-2) with an IC50 of 15 µM in A-549 cells. This compound induces G2/M cell cycle arrest and could also suppress the JAK/STAT signalling pathway. It can be isolated from Radix linderae.
E1510	Sonrotoclax	Sonrotoclax(BGB-11417) is a highly potent, orally active and selective inhibitor of Bcl2. This compound demonstrates increased potency along with in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant. Bcl-xL It has effective cell killing effect against a variety of lymphoma and leukemia cell lines.
S5600	Flavokawain A	Flavokawain A, extracted from kava, is an apoptotic inducers and anticarcinogenic agent. This compound can down-regulation of antiapoptotic proteins, such as XIAP, survivin, and Bcl-xL, thereby changing the balance between apoptotic and antiapoptotic molecules and then induce cell death in tumor cells.
S8177	BH3I-1	BH3I-1 is a Bcl-XL-BH3 domain interaction inhibitor with Ki of 2.4 μM (by fluorescence polarization ).This compound is a selective inhibitor of Bcl-2 family proteins.
S6004	CCI-007	CCI-007 is a novel small molecule with cytotoxic activity against infant leukemia with MLL rearrangements.
S8758	VU661013	VU661013 is a novel, potent, selective MCL1 inhibitor with Ki of 97 ± 30 pM of human MCL-1 in a TR-FRET assay. However, this compound does not significantly inhibit BCL-xL or BCL-2 with Ki > 40 μM or = 0.73 μM. It de-stabilizes BIM/MCL-1 association, leads to apoptosis in AML.	Gastric Cancer, 2025, 10.1007/s10120-025-01630-w
S8550	Tapotoclax (AMG-176)	Tapotoclax (AMG-176) is a potent, selective, and orally bioavailable macrocyclic inhibitor of MCL1 with a Ki of 0.13 nM. It induces a potent apoptosis in models of hematologic malignancies.
E2663	BT2	BT2 is a novel branched-chain α-ketoacid dehydrogenase complex kinase (BDK) inhibitor wieh an IC50 of 3.19 μM.
E5962New	BRD-810	BRD-810 is a potent and highly selective inhibitor of MCL1. BRD-810 targets the BH3-binding pocket of MCL1 and blocks the capturing of pro-apoptotic proteins, thereby rapidly triggering caspase activation in MCL1-dependent cells. It demonstrates potent anti-tumor effects in both hematologic malignancies and solid tumor models.
E3020	Hedyotic Diffusa Extract	Hedyotic Diffusa Extract is extracted from Hedyotic diffusa, of which polysaccharides inhibit the growth of CNE2 cells in a dose-and-time-dependent way, the mechanism may involve induction of cell apoptosis, which is associated with the activation of Bax and caspase-3 protein and the down-regulation of Bcl-2 protein expression.
S2606	Mifepristone (RU486)	Mifepristone is a remarkably active antagonist of progesterone receptor and glucocorticoid receptor with IC50 of 0.2 nM and 2.6 nM, respectively. Mifepristone promotes cell autophagy and apoptosis, decreases Bcl-2 level and increases Beclin1 level, accompanied by weakened interaction between Bcl-2 and Beclin1.Mifepristone (RU486) can be used to induce animal models of Spontaneous Abortion.	Pharmacol Res, 2025, 215:107696 Cell Death Dis, 2025, 16(1):237 J Virol, 2025, 99(2):e0147224
S8820	Unesbulin (PTC596)	Unesbulin (PTC596) is a second-generation BMI-1 inhibitor that accelerates BMI-1 degradation. This compound downregulates MCL-1 and induces p53-independent mitochondrial apoptosis. IC50 values at 72 hours ranged from 68 to 340 nM in mantle cell lymphoma (MCL) cell lines.	Cell Rep Med, 2025, S2666-3791(25)00150-8 NPJ Precis Oncol, 2024, 8(1):68 PLoS One, 2023, 18(2):e0277313
S6852	Gossypol	Gossypol (BL 193) is an orally-active polyphenol isolated from cotton seeds and roots. This compound is a potent inhibitor of 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase with IC50 of 3.33 μM and 0.52 μM in cell-free assay, respectively. It also inhibits the binding of BH3 peptide to Bcl protein with IC50 of 0.4 μM and 10 μM for Bcl-XL and Bcl-2, respectively. This chemical induces apoptosis and cell growth inhibition in various cancer cells.	iScience, 2024, 27(10):110862 Cells, 2023, 12(18)2247 Cells, 2023, 10.3390/cells12182247
S5967	Berberine chloride hydrate	Berberine (Natural Yellow 18) chloride hydrate is a quaternary ammonium salt from the group of isoquinoline alkaloids. Berberine activates caspase 3 and caspase 8, cleavage of poly ADP-ribose polymerase (PARP) and the release of cytochrome c. Berberine chloride decreases the expression of c-IAP1, Bcl-2 and Bcl-XL. Berberine chloride induces apoptosis with sustained phosphorylation of JNK and p38 MAPK, as well as generation of the ROS. Berberine chloride is a dual topoisomerase I and II inhibitor. Berberine chloride is also a potential autophagy modulator.	Front Biosci (Landmark Ed), 2022, 27(8):242 Front Pharmacol, 2021, 12:632201
E0124	Chelerythrine	Chelerythrine (Toddaline, Broussonpapyrine) is a potent, selective antagonist of PKC with an IC50 of 0.66 μM. This compound also inhibits the BclXL-Bak BH3 peptide binding with an IC50 of 1.5 μM. It shows antitumor, antidiabetic and anti-inflammatory activity.	Nutr Neurosci, 2022, 1-19
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.
S6895	TCPOBOP	TCPOBOP is a constitutive androstane receptor (CAR) agonist. This compound attenuates Fas-induced murine liver injury by altering Bcl-2 proteins.
E2354	Valepotriate	Valepotriate, an unstable iridoid isolated from Valeriana jatamansi Jones, has anti-epileptic by significantly increasing the expression of GABAA, glutamic acid decarboxylase 65, and Bcl-2 and reduce the expression of caspase-3.
S2271	Berberine chloride	Berberine chloride is a quaternary ammonium salt from the group of isoquinoline alkaloids. This compound activates caspase 3 and caspase 8, cleavage of poly ADP-ribose polymerase (PARP) and the release of cytochrome c. It decreases the expression of c-IAP1, Bcl-2 and Bcl-XL. This chemical induces apoptosis with sustained phosphorylation of JNK and p38 MAPK, as well as generation of the ROS. It is a dual topoisomerase I and II inhibitor. It is also a potential autophagy modulator.	J Cardiovasc Dev Dis, 2025, 12(7)278 Adv Healthc Mater, 2023, e2300591. Transl Oncol, 2023, 35:101712
S9665	Motixafortide (BKT140)	Motixafortide (BL-8040, BKT140, TF 14016, 4-fluorobenzoyl, 4F-benzoyl-TN14003, T140) is an antagonist of CXCR4 with IC50 of ～1 nM. BL-8040 induces the apoptosis of AML blasts by down-regulating ERK, BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression.	King's College London, 2023,
S8650	BTSA1	BTSA1 is a pharmacologically optimized BAX activator that binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis. It effectively promotes apoptosis in leukemia cell lines and patient samples while sparing healthy cells.	bioRxiv, 2024, 10.1101/2023.01.18.524628 Cell Mol Life Sci, 2023, 80(10):311 Cell Mol Life Sci, 2023, 80(10):311
S7105	BAM7	BAM 7 is a direct and selective activator of proapoptotic Bax with EC50 of 3.3 μM.	Nat Chem Biol, 2019, 15(4):322-330 Cell Death Discov, 2018, 4:107 Baltimore, Maryland , 2018,
S9276	Alisol B	Alisol B, a triterpene from Alismatis rhizoma, induces Bax up-regulation and nuclear translocation, the activation of initiator caspase-8 and caspase-9, and executor caspase-3, suggesting the involvement of both extrinsic and intrinsic apoptosis pathways.
S7747	Ro-3306	RO-3306 is an ATP-competitive, and selective CDK1 inhibitor with Ki of 20 nM, >15-fold selectivity against a diverse panel of human kinases. RO-3306 enhances p53-mediated Bax activation and mitochondrial apoptosis.	Nat Commun, 2025, 16(1):7898 Nat Commun, 2025, 16(1):6439 Nucleic Acids Res, 2025, 53(21)gkaf1179
S3275	Senkyunolide I	Senkyunolide I (SEI, SENI) is an orally active compound isolated from Ligusticum chuanxiong with analgesic, anti-migraine, neuroprotective, anti-oxidation and anti-apoptosis activities. This compound up-regulates the phosphorylation of Erk1/2 and induces Nrf2 nuclear translocation with enhanced HO-1 and NQO1 expressions. It also promotes the ratio of Bcl-2/Bax and inhibits the expressions of cleaved caspase 3 and caspase 9.	Blood Sci, 2025, 7(3):e00246 iScience, 2024, 27(7):110367 World J Emerg Med, 2024, 15(3):206-213
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
S5550	Ethyl gallate	Ethyl gallat (Phyllemblin, gallic acid ethyl ester), which could be found naturally in a variety of plant sources, is a food additive with antimicrobial activity. Ethyl gallat activates the death receptor-dependent pathway of apoptosis by enhancing the expression of caspases-8, -9, and -3 and the Bcl-2 interacting domain (Bid).	Front Pharmacol, 2024, 15:1403424
S1057	Obatoclax Mesylate (GX15-070)	Obatoclax Mesylate (GX15-070) is an antagonist of Bcl-2 with Ki of 0.22 μM in a cell-free assay, can assist in overcoming MCL-1 mediated resistance to apoptosis.	Nat Commun, 2025, 16(1):2416 bioRxiv, 2024, 10.1101/2023.01.18.524628 Emerg Microbes Infect, 2022, 1-29
S7100	WEHI-539	WEHI-539 has high affinity (IC50=1.1 nM) and selectivity for BCL-XL and potently kills cells by selectively antagonizing its prosurvival activity. This compound has more than a 400-fold higher affinity for BCL-XL versus other prosurvival BCL-2 family members.	bioRxiv, 2025, 2025.06.10.658786 Cell Rep Med, 2023, 4(11):101290 Leiden University The Netherlands, 2023,
S6709	Obatoclax (GX15-070)	Obatoclax (GX15-070) is an antagonist of Bcl-2 with an Ki of 0.22 μM in a cell-free assay, can assist in overcoming MCL-1 mediated resistance to apoptosis.	Signal Transduct Target Ther, 2025, 10(1):161 Oncotarget, 2024, 15:614-633 Cells, 2023, 12(18)2247
S7126	Marinopyrrole A (Maritoclax)	Maritoclax (Marinopyrrole A) is a selective Mcl-1 antagonist that binds to Mcl-1, but not Bcl-XL, and targets it for proteasomal degradation. This compound disrupts the interaction between Bim and Mcl-1 with an IC50 of 10.1 μM.	Clin Cancer Res, 2023, 29(2):446-457 Clin Cancer Res, 2023, 29(2):446-457 Cell Signal, 2022, S0898-6568(22)00041-9
S7849	BDA-366	BDA-366 is a small-molecule Bcl2-BH4 domain antagonist and binds BH4 with high affinity and selectivity. It directly binds to Bcl2 with high binding affinity (Ki =3.3 ± 0.73 nM).	Biochem Pharmacol, 2025, S0006-2952(25)00712-9 BMC Cancer, 2023, 23(1):479
S8199	Ruxotemitide (LTX 315)	Ruxotemitide (LTX 315) is the oncolytic peptide that kills cancer cells through Bax/Bak-regulated mitochondrial membrane permeabilization.	J Immunother Cancer, 2022, 10(3)e004129 Nat Metab, 2021, 10.1038/s42255-021-00491-8
S0563	10-Deacetyl-7-xylosyl paclitaxel	10-Deacetyl-7-xylosyl paclitaxel (10-Deacetyl-7-xylosyltaxol, 7-xylosyl-10-deacetylpaclitaxel), a derivative of paclitaxel and naturally occurring xyloside isolated from Taxus chinensis, causes significant mitotic arrest in PC-3 cells followed by up-regulating expression of pro-apoptotic Bax and Bad protein, as well as down-regulating expression of anti-apoptotic Bcl-2 and Bcl-XL , which leads to a disturbance of the mitochondrial membrane permeability and to the activation of caspase-9.	Cell Death Dis, 2022, 13-9:799
S3245	Nodakenetin	Nodakenetin (NANI), a plant-derived coumarin isolated from Angelica decursiva, inhibits α-glucosidase, PTP1B, rat lens aldose reductase (RLAR), AChE, BChE, and β-site amyloid precursor protein cleaving enzyme 1 (BACE1). This compound alters the protein expression of Bax and Bcl-2, and prompts mitochondrial apoptosis. It exhibits anti-tumor activity.
S3267	Nicotiflorin (Kaempferol-3-O-rutinoside)	Nicotiflorin (Kaempferol-3-O-rutinoside), a flavonoid extracted from Carthamus tinctorius, alters the shape and structure of injured neurons, decreases the number of apoptotic cells, down-regulates expression of p-JAK2, p-STAT3, caspase-3, and Bax and decreases Bax immunoredactivity, and increases Bcl-2 protein expression and immunoreactivity.
E2028	Humanin	Humanin (human) (1-24-Protein humanin (human)), a small mitochondrial-derived cytoprotective polypeptide encoded by mtDNA, exhibits protective effects in several cell types against cellular stress conditions and apoptosis through regulating various signaling mechanisms, such as JAK/STAT pathway and interaction of BCL-2 family of protein.
E8278New	WH244	WH244 is a second-generation PROTAC that selectively degrades the anti-apoptotic proteins BCL-xL and BCL-2 with a DC50 of 0.6 nM for BCL-xL and 7.4 nM for BCL-2.
E5962New	BRD-810	BRD-810 is a potent and highly selective inhibitor of MCL1. BRD-810 targets the BH3-binding pocket of MCL1 and blocks the capturing of pro-apoptotic proteins, thereby rapidly triggering caspase activation in MCL1-dependent cells. It demonstrates potent anti-tumor effects in both hematologic malignancies and solid tumor models.

Signaling Pathway Map

Bcl-2 (B-cell lymphoma 2) is encoded by the Bcl-2 gene and is the first identified member of a large family of apoptosis regulatory proteins (Bcl-2 family) that derives its name from the B-cell lymphoma 2, as it is the second member of a variety of proteins initially described in the t(14;18) chromosomal translocation in human follicular B-cell lymphomas. Bcl-2 contains four Bcl-2 homology domains (BH1-BH4) that mediate the formation of homodimer and heterodimer with relative proteins such as Bax, Bad, Bak and Bcl-xL, and a trans-membrane (TM) domain that mediates insertion into the outer membrane of the mitochondria and the endoplasmic reticulum. Bcl-2 proteins are generally integrated within the outer mitochondrial membrane (OMM), and may also be in the cytosol or ER membrane. The Bcl-2 and other antiapoptotic members of the Bcl-2 family preserve the outer mitochondrial membrane (OMM) integrity, thus inhibiting the mitochondrial signaling pathway of apoptosis, by complex interactions with the proapoptotic Bcl-2 proteins such as Bax, Bak, Bim, Puma and tBid. ^[1][2]

Bcl-2 suppresses apoptosis in response to a broad range of stress stimuli, including those frequently encountered during tumor development, such as oncogene activation, DNA damage, hypoxia (oxygen deprivation), loss of appropriate growth signals and anoikis (loss of cell attachment). In healthy cells, Bax and Bak are kept in check by the pro-survival Bcl-2 family members and the binding of BH3-only proteins unleashes Bax/Bak. Bcl-2 is also critical for the survival of renal epithelial stem cells during embryogenesis, melanocyte progenitors and mature B and T lymphocytes. Bcl-2 over-expression accelerates Eu-myc-induced lymphomagenesis, but loss of endogenous Bcl-2 does not prevent or delay Eu-myc-induced B lymphoma development. Bcl-2 proteins also constitutively binds to Beclin-1, and its dissociation through post-translational modification of Beclin-1 and/or Bcl-2 proteins such as phosphorylation by JNK1, or direct competition for the Bcl-2 BC groove by another BH3-only protein such as Bad, may be sufficient to induce autophagy, leading to the suggestion that autophagy and apoptosis are mechanistically linked. Single-site phosphorylation at Serine 70 (S70) is required for the antiapoptotic function of Bcl-2, and multisite phosphorylation at Threonine 69, S70, and S87 has been reported to inactivate Bcl-2. Phosphorylation of Bcl-2 has been shown to enhance activity to allow response to extracellular growth-factor-mediated signals. ^[1][2][3]

In addition, Bcl-2 is over-expressed in human follicular centre B-cell lymphoma; high levels of Bcl-2 are also detected in significant numbers of chronic lymphocytic leukaemia (CLL), DLBCL and mantle cell lymphoma, as well as in certain solid tumours(brain, breast and lung). The upregulation of Bcl-2 in CLL and other cancers has been attributed to the hypo-methylation of the Bcl-2 promoter or, possibly more importantly due to hemizygous or homozygous loss of the micro RNAs (miRs) 15a and 16-1 that negatively regulate Bcl-2. The dysregulated Bcl-2 proteins in cancer can lead to increased survival of abnormal cells, which are thought to be involved in resistance to conventional cancer treatment. Mice that constitutively express both Myc and Bcl-2 transgenes develop lymphoblastic leukaemia with high incidence, while shut-down of the inducible Bcl-2 transgene in lymphoma-burdened bi-transgenic mice results in tumor regression and significantly prolonged animal survival in many cases, indicating that inactivation of Bcl-2 constitutes a promising new approach to cancer therapy. Small molecule mimetics of BH3-only proteins that can directly target pro-survival Bcl-2 family members are being developed as a novel therapeutic approach. ABT-737 and the closely related orally bioavailable ABT-263, belong to the BH3 mimetic small molecule inhibitors, targeting Bcl-2 and Bcl-2-related proteins such as Bcl-xL and Bcl-w, therefore promoting tumor regression in murine xeno-transplanation models of certain human lymphomas or small cell lung carcinomas and in primary patient-derived follicular lymphoma cells. ^[1][4]