With the emergence of the tyrosine kinase inhibitors attention was directed toward Akt, a serine/ threonine kinase of the protein kinase family. Akt is more formally known as protein kinase B and exists in three isoforms. Its role in the cellular signaling cascades has been well documented with downstream effects on mTOR, BAD and GSK3 [1] The PI3K/Akt/mTOR pathway has been established as having an important role in apoptosis, cell migration and proliferation, transcription and glucose metabolism. In various known forms of malignancies Akt has been established as playing a crucial role, an elevated expression of phosphorylated Akt is a contraindication of survival.[2-4] Hence focus was placed on the development of AKT inhibitor drugs. AKT inhibition has been achieved with Perifosine, MK-2206, RX-0201, Erucylphosphocholine (ErPC), PBI-05204, GSK690693, A-443654 and XL-418.

AKT INHIBITORS: Pre-clinical and Clinical status

Perifosine is described as phospholipid derivative of alkylphosphocholine[5;6]. It is a inhibitor of the Akt pathway, but has also been reported to inhibit both the MAPK and JNK pathways as well [7-10]. It has demonstrated activity in murine models of neuroblastoma, in human squamous cell carcinoma xenograpghs, ovarian cancer murine models and in mammary carcinoma rat models [11-13]. Phase 1 trials have been conducted to determine MTD and safety of perifosine, it is reported that subsequent to a loading dose of 600 mg, 100 mg per day orally maintained systemic concentrations at a sufficient level.[14;15] Phase II trials have studied Perifosine in patients with soft tissue sarcoma, prostate cancer, pancreatic adenocarcinoma, metastatic head and neck cancer and in metastatic melanoma. [16] but results have been disappointing in that little response a the dosing levels tested was seen. Perifosine as a single agent does not improve therapy, however, combination with bortezomib and dexamethasone, cetuximab, rapamycin or radiation has demonstrated some more positive responses. [17] Perifosine in combination with radiation has moved to a phase 3 trial status with the report being due in 2013.


MK-2206 functions as an allosteric inhibitor of Akt. As a result of this MK-2206 enhances the action of more traditional chemotherapy agents.[18] Pre clinically MK-2206 demonstrates activity in breat cancer models, lung cancer models and in head/neck cancer models when in combination with first line chemotherapy agents. Phase 1 trials have established MTD and pharmacokinetic profiles but limit phase 2 trials have been initiated to data.[19] This molecule is relatively new to the research arena and has yet to be fully investigated.


RX-0201 is an anti-sense form of inhibitor. Antisense nucleic acid molecules are used to bind to mRNA and prevent expression of specific genes. This process is based a naturally occurring phenomem whereby cells produce antisense RNA molecules to interact with mRNA thereby inhibiting expression.[20;21] RX-0201 is a relatively new molecule and little is currently in literature but pre-clinically RX-0201 has resulted in growth inhibition of a variety of human cell lines while in murine models of glioblastoma substantial growth inhibition was reported. In line with the encouraging response seen pre-clinically phase 1 and phase 2 trials are currently being implemented.

Erucylphosphocholine (ErPC)

As a structural derivative of perifosone ErPC is being studied pre-clinically in the treatment of malignant brain tumors. It has been shown to induce apoptosis in cells previous resistant to traditional chemotherapy, exhibiting a strong negative correlation between concentration and tumor volume.[22;23] Mechanistic investigations demostrated that ErPC initiated the intrinsic caspase cascade leading apoptosis, this was not affected by TNF or TRAIL inhibition.[24;25] Further work suggests that ErPC also inhibits the MAP and JNK pathways.[26] ErPC has been tested on Ovarian and choriocarcinoma cell lines with promising results when considering apoptosis is observed in tumor cells but not in the equivalent normal cell lines. [27;28]


PBI-05204 is an inhibitor Akt, fibroblast growth factor 2 (FGF2), NF-kappa B and p70S6K and is currently in development [29;30]. Limited data is available but phase 1 trials in bladder, colorectal and fallopian tube carcinoma are ongoing with interim reports of stable disease lasting for 4 months at the time of the reports issue.


GSK690693 has been observed to inhibit all isoform of Akt with sensitivities in the nM range. In murine ovarian models, prostate models and breast tumor models significant growth inhibition has been observed [31-33]. Unfortunately a phase 1 trial with GSK690693 in solid tumors and lymphoma’s was halted prematurely with no reasoning being published. To date no trials are being conducted and a phase 1 trial in hematological malignancies has been withdrawn.


L-418 was a dual inhibitor of Akt and p70S6K which was assessed in a phase I clinical trial for advanced solid tumors, this trial was halted prematurely due to poor pharmacokinetic profile. No further trials have been planned.

AKT pathway inhibitors: Availability

The AKT selective inhibitors are readily available for research with high purity and low costs from a variety of sources. AKT antagonists are being used systematically to isolate the mechanisms behins the PI3/Akt/mTOR pathway so researchers can still buy AKT inhibitors with no further clinical applicability for research laboratory uses.


1. Mattmann ME, Stoops SL et al. Inhibition of Akt with small molecules and biologics: historical perspective and current status of the patent landscape. Expert Opin Ther Pat 2011; 21(9):1309-1338.

2. Koseoglu S, Lu Z et al. AKT1, AKT2 and AKT3-dependent cell survival is cell line-specific and knockdown of all three isoforms selectively induces apoptosis in 20 human tumor cell lines. Cancer Biol Ther 2007; 6(5):755-762.

3. Maroulakou IG, Oemler W et al. Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. Cancer Res 2007; 67(1):167-177.

4. Sun M, Fuentes SM et al. Akt plays a critical role in replication of nonsegmented negative-stranded RNA viruses. J Virol 2008; 82(1):105-114.

5. Knebel NG, Grieb S et al. Quantification of perifosine, an alkylphosphocholine anti-tumour agent, in plasma by pneumatically assisted electrospray tandem mass spectrometry coupled with high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1999; 721(2):257-269.

6. Zeisig R, Arndt D et al. Physical properties and pharmacological activity in vitro and in vivo of optimised liposomes prepared from a new cancerostatic alkylphospholipid. Biochim Biophys Acta 1998; 1414(1-2):238-248.

7. Gills JJ, Dennis PA. Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep 2009; 11(2):102-110.

8. Hideshima T, Catley L et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 2006; 107(10):4053-4062.

9. Ruiter GA, Zerp SF et al. Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. Cancer Res 1999; 59(10):2457-2463.

10. Ruiter GA, Zerp SF et al. Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway. Anticancer Drugs 2003; 14(2):167-173.

11. de Vries NA, Beijnen JH et al. High-grade glioma mouse models and their applicability for preclinical testing. Cancer Treat Rev 2009; 35(8):714-723.

12. Li Z, Tan F et al. In vitro and in vivo inhibition of neuroblastoma tumor cell growth by AKT inhibitor perifosine. J Natl Cancer Inst 2010; 102(11):758-770.

13. Wu R, Hu TC et al. Preclinical Testing of PI3K/AKT/mTOR Signaling Inhibitors in a Mouse Model of Ovarian Endometrioid Adenocarcinoma. Clin Cancer Res 2011; 17(23):7359-7372.

14. Van UL, Binger K et al. A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer. Clin Cancer Res 2004; 10(22):7450-7456.

15. Crul M, Rosing H et al. Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours. Eur J Cancer 2002; 38(12):1615-1621.

16. Knowling M, Blackstein M et al. A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: A National Cancer Institute of Canada Clinical Trials Group trial. Invest New Drugs 2006; 24(5):435-439.

17. Holland WS, Tepper CG et al. Evaluating rational non-cross-resistant combination therapy in advanced clear cell renal cell carcinoma: combined mTOR and AKT inhibitor therapy. Cancer Chemother Pharmacol 2012; 69(1):185-194.

18. Hirai H, Sootome H et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 2010; 9(7):1956-1967.

19. Cheng Y, Zhang Y et al. MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis. Mol Cancer Ther 2011.

20. Pal SK, Reckamp K et al. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 2010; 19(11):1355-1366.

21. Li Q. Recent progress in the discovery of Akt inhibitors as anticancer agents. Expert Opinion on Therapeutic Patents 2007; 17(9):1077-1130.

22. Erdlenbruch B, Jendrossek V et al. Antitumor effects of erucylphosphocholine on brain tumor cells in vitro and in vivo. Anticancer Res 1998; 18(4A):2551-2557.

23. Erdlenbruch B, Jendrossek V et al. Erucylphosphocholine: pharmacokinetics, biodistribution and CNS-accumulation in the rat after intravenous administration. Cancer Chemother Pharmacol 1999; 44(6):484-490.

24. Kugler W, Buchholz F et al. Downregulation of Apaf-1 and caspase-3 by RNA interference in human glioma cells: consequences for erucylphosphocholine-induced apoptosis. Apoptosis 2005; 10(5):1163-1174.

25. Kugler W, Erdlenbruch B et al. Erucylphosphocholine-induced apoptosis in glioma cells: involvement of death receptor signalling and caspase activation. J Neurochem 2002; 82(5):1160-1170.

26. Kugler W, Erdlenbruch B et al. MAP kinase pathways involved in glioblastoma response to erucylphosphocholine. Int J Oncol 2004; 25(6):1721-1727.

27. Takai N, Ueda T et al. Erucylphosphocholine shows a strong anti-growth activity in human endometrial and ovarian cancer cells. Gynecol Oncol 2008; 111(2):336-343.

28. Takai N, Ueda T et al. Erucylphosphocholine induces growth inhibition, cell cycle arrest, and apoptosis in human choriocarcinoma cells. Tumour Biol 2011; 32(3):569-574.

29. Dunn DE, He DN et al. In vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke models. J Neurochem 2011; 119(4):805-814.

30. Pal SK, Reckamp K et al. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 2010; 19(11):1355-1366.

31. Carol H, Morton CL et al. Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program. Pediatr Blood Cancer 2010; 55(7):1329-1337.

32. Altomare DA, Zhang L et al. GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt. Clin Cancer Res 2010; 16(2):486-496.

33. Levy DS, Kahana JA et al. AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood 2009; 113(8):1723-1729.

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S1037 Perifosine (KRX-0401) Perifosine (KRX-0401) is a novel Akt inhibitor with IC50 of 4.7 μM in MM.1S cells, targets pleckstrin homology domain of Akt. Phase 3. (72) (16)
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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. Phase 1. (33) (5)

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