Covalent inhibitors of the RAS binding domain of PI3Ka impair tumor growth driven by RAS and HER2

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 D. Lin; Yongsheng Liu; Marie Pariollaud; Holly Parker; Igor Mochalkin; Sareena Rana; Aaron Nathan Snead; Eric Walton; Taylor E. Wyrick; Erick W. Aitchison; Karl Bedke; Jacyln C. Brannon; Joel M. Chick; Kenneth Hee; Benjamin D. Horning; Mohamed Ismail; Kelsey N. Lamb; Lin Wei; Justine Lu; Martha Katherine Pastuszka

doi:10.1126/science.adv2684

Cancer BiologyScienceOct 9, 2025

Peer-reviewed journal article

Covalent inhibitors of the RAS binding domain of PI3Ka impair tumor growth driven by RAS and HER2

Joseph E. Klebba iD, Nilotpal Roy iD, Steffen M. Bernard iD, Stephanie Grabow iD, Melissa A. Hoffman iD, Hui Miao iD, Junko Tamiya iD, Jinwei Wang iD, Cynthia Berry iD, Antonio Esparza-Oros iD, Richard D. Lin iD, Yongsheng Liu iD, Marie Pariollaud iD, Holly Parker iD, Igor Mochalkin, Sareena Rana iD, Aaron Nathan Snead iD, Eric Walton iD, Taylor E. Wyrick, Erick W. Aitchison iD, Karl Bedke iD, Jacyln C. Brannon iD, Joel M. Chick, Kenneth Hee iD, Benjamin D. Horning iD, , Matthew P. Patricelli iD

Abstract

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 p110 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.

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