biostudies-literatureKlebba JEMedical Research Council CanadaU.S. Department of EnergyCancer Research UKEuropean Research CouncilMedical Research CouncilUniversity of KentuckyWellcome TrustNIGMS NIH HHS702-709https://www.ebi.ac.uk/biostudies/studies/S-EPMC7618302biostudies-literatureUnknown390(6774)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 kinScience (New York, N.Y.)Covalent inhibitors of the PI3Kα RAS binding domain impair tumor growth driven by RAS and HER2.PMC7618302CC2097FC001070P30 GM12416905CH11231DE-AC02Rana SMolina-Arcas MLin RTamiya JIsmail MMiao HMochalkin ILin WDownward JWang JSnead ANAitichson EBedke KSimon GMHoffman MAYue CLiu YHorning BDEsparza-Oros ALamb KNWyrick TEPariollaud MRoy NGrabow SWalton EJBrannon JCSigler JJBerry CParker HPatricelli MPChick JMKlebba JEHee KLu JKinsella TMWeinstein DSBernard SMTomaschko MTran ECook BNPollock JPastuszka MKfalseCovalent inhibitors of the PI3Kα RAS binding domain impair tumor growth driven by RAS and HER2.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 kin2025-01-01T00:00:00Z2025 Nov2026-06-11T05:24:58.156Z2026-06-11T03:08:15.067ZS-EPMC76183024106654110.1126/science.adv2684