AKT pathway inhibitors with an undefined mechanism of action

9-Methoxy-2-methylellipticinium acetate (API-59-OMe, 24) has previously been reported as an AKT kinase pathway inhibitor in human endometrial cancer cells [36]. Similar results have been shown with 24 in ovarian cancer cell lines (A2780, MDAH2774 and OVCAR-8) [37]. The A2780 and MDAH2774 lines have high levels of activated AKT, while OVCAR-8 exhibits endogenous amplification and expression of AKT-2. Treatment of the cells with 24 significantly inhibited AKTmediated phosphorylation of Bad at Ser136 and GSKa/p at Ser21/9 as measured by an IP kinase assay. Chloro-2-methylellipticinium acetate (CMEP, 25) was profiled against a series of prostate cancer lines (Cl-1, LNCaP and PC-3) having high basal levels of AKT inhibition [38]. In these cell lines, 25 significantly reduced AKT-mediated phosphorylation as measured by an IP kinase assay. Compound 25 also induced apoptosis in these cells when dosed at 10 pM.

KP372-1 (26) consists of a 1:1 mixture of indenotetrazolotriazinones, representative of a novel class of fused polycyclic compounds that suppress AKT activity via an unknown mode of action. There have been several reports describing induction of apoptosis and inhibition of cell proliferation by 26 in cancer cells having high levels of AKT activation. For example, 26 induces apoptosis in thyroid cancer cells (NPA187, IC50 = 30 nM; WRO, IC50 = 60 nM) by blocking the phosphorylation and kinase activity of AKT [39]. Similar findings were observed with 26 in U251 and U87 glioma cells [40]. Compound 26 was also described as a dual AKT/PDK1 kinase inhibitor in leukemic cells [41]. Compound

26 almost completely inhibited AKT and PDK1 kinase activity in vitro. In addition, 26 caused mitochondrial dysfunction and led to apoptosis in several acute myelogenous leukemia cell lines, but not in normal hematopoietic progenitor cells.

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