John M Ketcham, Stephen J Harwood, Ruth Aranda, Athenea N Aloiau, Briana M Bobek, David M Briere, Aaron C Burns, Kersti Caddell Haatveit, Andrew Calinisan, Jeffery Clarine, Adam Elliott, Lars D Engstrom, Robin J Gunn, Anthony Ivetac, Benjamin Jones, Jon Kuehler, J David Lawson, Natalie Nguyen, Cody Parker, Kelly E Pearson, Lisa Rahbaek, Barbara Saechao, Xiaolun Wang, Anna Waters, Laura Waters, Ashlee H Watkins, Peter Olson, Christopher R Smith, James G Christensen, Matthew A Marx
The H1047R mutation of PIK3CA is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3KαH1047R over PI3KαWT is crucial due to the role that PI3KαWT plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3KαH1047R -selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3KαH1047R with high selectivity over PI3KαWT , resulting in the discovery of compound 17 ...
March 13, 2024: Journal of Medicinal Chemistry