Pi3kakt Kinase Pathway Inhibitors In Clinical Trials

Perifosine (27) is a synthetic, orally available alkylphospholipid, derived from alkylphosphocholine, which targets the PI3/AKT survival pathway. Although the molecular mechanism underlying the antineoplastic activity of 27 is not fully elucidated, studies suggest that 27 interferes with turnover and synthesis of natural phospholipids. This disrupts membrane signaling at several sites resulting in the inhibition of the PI3K/AKT survival pathway [42,43]. Recent preclinical evaluation in cultured human Jurkat T-leukemia cells has shown that adding low concentrations of 27 (5 mM) after treatment with the commonly used chemotherapy drug etoposide, induced cell death in a synergistic fashion. The observed increase in cell death is attributed to an inactivation of the AKT survival pathway, as treated cells showed a complete dephosphorylation of AKT [44]. Compound 27 also inhibited baseline phosphorylation of AKT in multiple myeloma cells in a time- and dose-dependent fashion [45]. Reduced tumor growth and increased survival was also observed in a murine multiple myeloma mouse model. In this study, administration of 27 at low concentrations (2.5-5 mM) with subtoxic concentrations of the conventional therapeutic agents dexamethasone, melphalan and bortezomib resulted in an enhanced cytotoxic effect in a dose-dependent fashion. Compound 27 is currently among the most clinically advanced small molecule AKT inhibitors as it has progressed to clinical evaluation for the treatment of many human cancers. Recently reported results from clinical trials involving 27 (either as single agent or in combination) have demonstrated clinical responses and antitumor activity in multiple myeloma, hormone-sensitive prostate cancer and non-small cell lung cancer (NSCLC) [46-50]. Adverse events associated with 27 include gastrointestinal irritation, fatigue and rash.

Triciribine (API-2, TCN, 28a) is a tricyclic nucleoside first reported in 1980 [51]. While 28a and the corresponding 5-phosphate derivative (triciribine phosphate, TCN-P, 28b) have demonstrated antitumor activity and progressed to clinical evaluation for the treatment of several advanced solid tumors, severe side effects (e.g. hepatotoxicity and hyperglycemia) related to dosing levels ultimately limited their use [52-59]. More recently, screening of the National Cancer Institute Diversity Set identified 28a as a highly selective inhibitor of AKT, wherein cell growth was suppressed at a concentration of 50 nM [60]. While it is known that 28a blocks the AKT pathway, the mechanism by which it prevents AKT activation has not been established. Additional preclinical findings report that 28a, at a dose of 5 p.M, effectively and selectively induced apoptosis and cell growth arrest in tumor cells in which AKT was aberrantly expressed or activated, while cancer cells without this trait were not affected [50,61]. In xenograft studies, no detectable side effects were observed in mice treated with 28a at 1 mg/kg/day, a dose in which tumor growth was significantly inhibited in cancer cells overexpressing AKT. Another preclinical study demonstrated that treatment with 28a reduced melanoma cell survival in a time-and dose-dependent manner. Phospho-AKT levels were decreased in these cells in response to 28a [62]. Treatment of the human melanoma cell lines, MMRU and MMAN, with 28a (5 mM for 48 h) inhibited cell survival by 35% and 45%, respectively, when compared to vehicle control. In a mouse tumor xenograft model, low concentrations of 28a, in combination with a recombinant adenovirus containing human PUMA cDNA (ad-PUMA), resulted in enhanced cooperative growth inhibition of human melanoma cells.

Thalidomide has been re-evaluated in recent years for the treatment of a broad spectrum of diseases despite its known teratogenic properties [63]. The thalidomide analog and immunomodulatory compound CC-5013 (29) is in phase III clinical evaluation for the treatment of patients with relapsed and refractory multiple myeloma [64]. Although the exact mechanism of action in a neoplastic setting is unknown, it has been suggested that the anti-tumor effect is related to anti-angiogenic potency, through inhibition of growth-factor-induced AKT phosphorylation [65]. When orally administered in rats, 29 inhibited bFGF induced phosphorylation of AKT in a dose-dependent manner [65]. Using an in vivo rat mesenteric window assay, 29 was shown to inhibit growth-factor-induced angiogenesis by inhibiting vascularization in a dose-dependent manner. Adverse side effects were not noted in this study. A pharmacokinetic study revealed that a single oral administration of 29 at 50mg/kg produced plasma drug concentrations comparable to levels that are required to inhibit angiogenesis in the human assay in vitro.

The thalidomide analogs CPS49 (30) and CPS11 (31) have been reported to inhibit PI3/AKT signaling in multiple myeloma cells via an anti-angiogenic effect. These compounds are devoid of the teratogenic properties seen with thalidomide and are currently in preclinical development [66]. Compound 30, and to a lesser extent 31, induced a dose-dependent inhibition of proliferation in several multiple myeloma cell lines and reduced phospho-AKT levels [66]. These compounds also inhibited DNA synthesis in cell lines resistant to conventionally used anti-multiple myeloma drugs (e.g. dexamethasone, anthracyclines and melphalan) in a dose-dependent manner.

In addition to small molecule therapies, oligonucleotides as AKT inhibitors are being investigated [67,68]. The 20-mer antisense oligonucleotide RX-0201, which is complementary to AKT-1 mRNA, has been reported to block AKT-1 activity and suppress cell proliferation in a number of carcinomas [69]. RX-0201 is active against 10 different AKT-1 overexpressing cell lines and demonstrated in vivo efficacy in mouse tumor xenograft models as measured by decreased tumor weight and increased survival time. No adverse side effects were noted. RX-0201 is currently in clinical trials for the treatment of patients with advanced or metastatic solid tumors [70], and has received orphan drug status from the FDA for the treatment of renal cell carcinoma, glioblastoma, ovarian, stomach and pancreatic cancers.

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