Discovery of Novel AKT Inhibitors with Enhanced Anti-Tumor Effects in Combination with the MEK Inhibitor

Abstract

Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.

Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398

“…Resistant lines demonstrated significantly reduced phosphorylation of GSK3β (S9), and GSK3α/β (S21/S9), the downstream targets of Akt. Interestingly, increased phosphorylation of Akt (S473 and T308) was observed in both the resistant cell lines with GSK2141795 treatment, likely due to feedback increase in Akt phosphorylation as previously described (21, 22). Overall, these results suggest that Akt pathway activation can mediate acquired resistance to FGFR targeting and Akt inhibitor treatment can restore sensitivity.…”

Dose-Finding Quantitative 18F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with Gynecologic Malignancies

“…GSK2141795 is an oral nanomolar pan-AKT kinase inhibitor that influences glucose uptake and inhibits cellular proliferation in some cell lines and xenograft models (25). The purpose of this trial was to explore whether GSK2141795 could decrease tumor glucose metabolism and whether a relationship could be established between changes in glucose metabolism in tumors (measured with 18 F-FDG PET) and PK parameters.…”

BAY 1125976, a selective allosteric AKT1/2 inhibitor, exhibits high efficacy on AKT signaling‐dependent tumor growth in mouse models

“…Perifosine is an unspecific inhibitor of AKT and therefore, the prevalence of side effects might be increased. A class of ATP‐competitive pan‐AKT inhibitors, such as AZD5363 (AstraZeneca), GSK2110183 and GSK2141795 (GlaxoSmithKline) and GDC‐0068 (Genentech) have shown encouraging results in preclinical experiments . In addition, AZD5363 has shown clinical responses in monotherapy in breast and gynecological cancer patients with PIK3CA or AKT1 mutations as reported recently .…”