Covalent 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 kinase pathway, without causing hyperglycemia.

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Publication Details

Journal
Science
Published
2025-10-09
DOI
https://doi.org/10.1126/science.adv2684
Citations
3
Primary Topic
PI3K/AKT/mTOR signaling in cancer
Type
article
Field-Weighted Citation Impact
2.42
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article

Covalent inhibitors of the PI3Kα RAS binding domain impair tumor growth driven by RAS and HER2

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Science
PI3K/AKT/mTOR signaling in cancer
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article

Covalent inhibitors of the PI3Kα RAS binding domain impair tumor growth driven by RAS and HER2

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article en
3 citations

Abstract

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.

ScienceVol. 390(6774)
The Francis Crick Institute (GB), Vividion Therapeutics (United States) (US), Odyssey School (US)
Openalex Percentile: Top 10%
PI3K/AKT/mTOR signaling in cancer
2.42
DOIOpen Access PDFOpenAlex
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