Joseph E. Klebba, Nilotpal Roy, Steffen M. Bernard, Stephanie Grabow, Melissa Hoffman, Hui Miao, Junko Tamiya, Jinwei Wang, Cynthia Berry, Antonio Esparza-Oros, Richard D. Lin, Yongsheng Liu, Marie Pariollaud, Holly Parker, Igor Mochalkin, Sareena Rana, Aaron N. Snead, Eric Walton, Taylor E. Wyrick, Erick Aitchison, Karl Bedke, Jacyln C. Brannon, Joel M. Chick, Kenneth Hee, Benjamin D. Horning, Mohamed Ismail, Kelsey N. Lamb, Lin Wei, Justine Lu, Martha K. Pastuszka, Jonathan Pollock, J. Sigler, Mona Tomaschko, Eileen Tran, Chanyu Yue, Todd M. Kinsella, Míriam Molina‐Arcas, Brian N. Cook, Gabriel M. Simon, David S. Weinstein, Julian Downward, Matthew P. Patricelli
Genetic disruption of the RAS binding domain (RBD) of phosphoinositide 3-kinase alpha (PI3Kα) impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not affect PI3Kα's role in insulin-mediated control of glucose homeostasis. Selectively blocking the RAS-PI3Kα interaction may represent a strategy for treating RAS-dependent cancers as it avoids the toxicity associated with inhibitors of PI3Kα lipid kinase activity. We developed compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block RAS activation of PI3Kα activity. In mice, inhibitors slow the growth of RAS mutant tumors and human epidermal growth factor receptor 2-overexpressing tumors, particularly when combined with other inhibitors of the RAS/mitogen-activated protein kinase pathway, without causing hyperglycemia.