Abstract 4476: BAY 80-6946, a highly selective and potent pan class I PI3K inhibitor induces tumor apoptosis in vitro and tumor regression in vivo in a sub-set of tumor models
Authors: Liu Ningshu , Rowley Bruce , Schneider Claudia , Bull Cathy , Kaekoenen Sanna , Hentemann Martin , Scott William , Mumberg Dominik , Ziegelbauer Karl 
Published: February 2011

We report on BAY 80-6946, a highly selective and potent pan class I PI3K inhibitor currently in Phase I clinical trials. The PI3K pathway is aberrantly activated in many tumors either by growth factor receptor tyrosine kinases, or by the genetic mutation and amplification of key pathway components. In biochemical assays BAY 80-6946 inhibits class I PI3K isoforms at sub- or low single digit nM IC50 values, while it is inactive against ∼240 protein/lipid kinases and receptors. This selective class I PI3K Inhibitor has a potent and distinct cellular response profile as compared to other PI3K inhibitors currently in early clinical development, such as the PI3K/mTOR dual inhibitor BEZ235 and the PI3K selective inhibitor GDC-0941. Among ∼140 tumor cell lines (covering 14 cancer indications) tested, BAY 80-6946 potently blocked the cell proliferation in ∼60 tumor cell lines with IC50 values of 1-100 nM. Mechanistically, BAY 80-6946 showed a robust activity inhibiting the phosphorylation of AKT at both Thr308 and Ser473 (IC50&lt;1 nM), as well as downstream phosphorylation of: PRAS40, 4E-BP1 and FOXOs (IC50&lt;10 nM) in PIK3CA mutant tumor cells. This indicates that disruption of PI3K signaling is the key mechanism of action underlying the inhibition of tumor cell growth and survival by BAY 80-6946. More importantly, BAY 80-6946 induced strong apoptosis in a sub-set of PIK3CA mutant tumors (such as BT20 and BT474, &gt; 3-fold caspase activation at the concentrations &lt;100 nM). Although BEZ235 and GDC-0941 effectively inhibited the proliferation of these breast cancer cell lines (IC50 values ranging from 5 to 50 nM for BEZ-235 and from 300 to 2000 nM for GDC-0941), neither drug was capable of inducing significant apoptosis (&gt; 3 fold caspase activation) at concentrations up to 10 μM at 72 hours. These results suggests that BAY 80-6946 significantly differs from BEZ235 and GDC-0941 with respect to induction of tumor cell apoptosis in selected breast cancer cell lines with PI3K mutations. In addition to the effects on tumor cells, BAY 80-6946 also exhibited potent anti-angiogenic properties by effectively blocking VEGF signaling both in vitro and in vivo. Finally, BAY 80-6946 was highly efficacious in multiple tumor xenograft models of different histological types with PI3CA mutations or PTEN deletions. In the rat KPL-4 breast tumor model (PIK3CAH1047R and HER2O/E (protein levels)), treatment with BAY 80-6946 resulted in durable complete tumor regressions after Q2Dx5 i.v. dosing schedule. In conclusion, BAY 80-6946 is a promising, highly selective and potent class I PI3K inhibitor currently in phase I clinical trials.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4476.