Discovery of Pyridopyrimidinones that Selectively Inhibit the H1047R PI3Kα Mutant Protein

The H1047R mutation of PIK3CA is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3K alpha(H1047R )over PI3K alpha(WT) is crucial due to the role that PI3K alpha(WT) plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3K alpha(H1047R)-selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3K alpha inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3K alpha(H1047R) with high selectivity over PI3K alpha(WT), resulting in the discovery of compound 17. When dosed in the HCC1954 tumor model in mice, 17 provided tumor regressions and a clear pharmacodynamic response. X-ray cocrystal structures from several PI3K alpha inhibitors were obtained, revealing three distinct binding modes within PI3K alpha(H1047R )including a previously reported cryptic pocket in the C-terminus of the kinase domain wherein we observe a ligand-induced interaction with Arg1047.