Abstract 3751: In vitro and in vivo pharmacological profile of BAY 1001931, a novel highly potent allosteric AKT1/2 inhibitor
Authors: Haegebarth Andrea , Politz Oliver , Liu Ningshu , Ince Stuart , Neuhaus Roland , Boemer Ulf , Gekeler Volker , Hoelder Swen , Zuelch Armin , Mumberg Dominik , Brands Michael , Ziegelbauer Karl 
Published: August 2012

Abstract
The PI3K/AKT/mTOR pathway is essential for tumor growth, proliferation, survival, invasion and metastasis. AKT, a central switch in this pathway, is deregulated in a broad range of refractory and primary tumors. Importantly, activation of AKT is one of the major mechanisms by which tumors escape from and become resistant to chemo-, radio- and targeted therapies. We report on preclinical studies of BAY 1001931, a highly selective and potent allosteric AKT1/2 inhibitor. In biochemical assays, BAY 1001931 inhibits AKT1 and AKT2 with similar potency (IC50 = 16 nM) while it displays weak activity against AKT3 (IC50 ∼ 1 µM) and is inactive against ∼230 other protein/ lipid kinases. Mechanistically, BAY 1001931 blocks AKT signalling by inhibiting the phosphorylation of AKT at both Thr308 and Ser473 (IC50 = 3.3 / 5.5 nM) as well as downstream phosphorylation of 4E-BP1 (IC50 = 70 nM). The strong inhibition of cellular p-AKT translates to a selective inhibition of tumor cell proliferation in vitro. Cell lines carrying defects in the tumor suppressor PTEN or oncogenic mutations in PIK3CA are most sensitive to BAY 1001931 treatment. Moreover, characterization of BAY 1001931 in a broader breast and prostate cancer cell line panel indicated strongest anti-proliferative efficacy in luminal and HER2 positive breast cancer cell lines and in androgen sensitive prostate cancer cell lines. In vitro combination profiling showed synergistic anti-proliferative effects with anti-hormonal therapeutics in breast and prostate cancer cell lines. When dosed orally in human xenograft tumor models, BAY 1001931 induced strong pharmacodynamic inhibition of AKT phosphorylation that correlated with drug exposure. BAY 1001931 was highly efficacious in multiple xenograft tumor models of different histological types with PIK3CA mutations or PTEN deletions. In tumor models predicted to be dependent on activated AKT signalling such as the KPL4 breast tumor model (PIK3CA H1047R and HER2 overexpression), daily oral treatment with BAY 1001931 induced tumor stasis or regression at well tolerated doses. Most importantly, when combined with anti-hormonal therapies such as tamoxifen in PIK3CA breast cancer xenograft models or bicalutamide or abiraterone acetate in PTEN deleted prostate cancer xenograft models, enhanced anti-tumor efficacy with durable tumor regressions were observed. In conclusion, BAY 1001931 is a highly selective, potent allosteric AKT1/2 inhibitor with strong in vitro and in vivo activity in tumor models with activated AKT signalling and strong synergistic activity in combination with anti-hormonals in breast and prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3751. doi:1538-7445.AM2012-3751