BAY-1125976

A potent and highly selective, allosteric AKT1/2 inhibitor with IC50 of 5.2/18 nM at 10 uM ATP; binds to active AKT1 with Kd of 2.7 nM and inactive AKT1 with Kd of 1.3 nM. displays >86-fold less potent against AKT3; inhibits the phosphorylation of AKT1 at T308 and S473 (IC50=0.9 and 1.1 nM, respectively), PRAS40 at T246 and 4EBP1 at T70; targets tumors displaying PI3K/AKT/mTOR pathway activation, inhibits cell proliferation in a broad panel of human cancer cell lines, particularly in breast and prostate cancer cell lines expressing estrogen or androgen receptors; exhibits strong in vivo patient-derived xenograft models.Solid Tumors Phase 1 Clinical (In Vitro) :BAY 1125976 is equally potent against Akt1 (IC50=5.2 nM at 10 μM ATP and 44 nM at 2 mM ATP) and Akt2 (IC50=18 nM at 10 μM ATP and 36 nM at 2 mM ATP) isoforms and up to 86 fold less potent against Akt3 (IC50=427 nM at 10 μM ATP) . It inhibits the Akt1 and Akt2 by binding into an allosteric binding pocket formed by kinase and PH domain. It inhibits cell proliferation in a broad panel of human cancer cell lines, particularly in breast and prostate cancer cell lines expressing estrogen or androgen receptors. It effectively blocks Akt signaling by inhibiting the phosphorylation of Akt and the downstream effectors, including eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), glycogen synthase kinase 3 beta (GSK3s), proline-rich Akt substrate 40 kDa (PRAS40), S6 ribosomal protein (S6RP), and 70 kDa ribosomal protein S6 kinase 1 (70S6K) . (In Vivo) :BAY 1125976 targets tumors displaying activation of the PI3K/Akt/mTOR pathway. BAY 1125976 exhibits strong in vivo efficacy in both cell line and patient-derived xenograft models such as the KPL4 breast cancer model (PIK3CAH1074R mutant), the MCF7 and HBCx-2 breast cancer models, and the AktE17K mutant driven prostate cancer (LAPC-4) and anal cancer (AXF 984) models.