Joseph E Klebba, Nilotpal Roy, Steffen M Bernard, Stephanie Grabow, Melissa A. Hoffman, Hui Miao, Junko Tamiya, Jinwei Wang, Cynthia Berry, Antonio Esparza-Oros, Richard Lin, Yongsheng Liu, Marie Pariollaud, Holly Parker, Igor Mochalkin, Sareena Rana, Aaron N. Snead, Eric J. Walton, Taylor E. Wyrick, Erick Aitichson, Karl Bedke, Jacyln C. Brannon, Joel M. Chick, Kenneth Hee, Benjamin D. Horning, Mohamed Ismail, Kelsey N. Lamb, Wei Lin, Justine Metzger, Martha K. Pastuszka, Jonathan Pollock, John J. Sigler, Mona Tomaschko, Eileen Tran, Todd M. Kinsella, Miriam Molina-Arcas, Gabriel M. Simon, David S. Weinstein, Julian Downward, Matthew P. Patricelli
bioRxiv 2024.12.17.629001;
doi: https://doi.org/10.1101/2024.12.17.629001
Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3Ks role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110a and block the ability of RAS to activate PI3K activity. These inhibitors have a profound impact on the growth of RAS mutant and also HER2 over-expressing tumors, particularly when combined with other inhibitors of the RAS/MAPK pathway, without causing hyperglycemia.
