1. Academic Validation
  2. Covalent inhibitors of the PI3Kα RAS binding domain impair tumor growth driven by RAS and HER2

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

  • Science. 2025 Nov 13;390(6774):702-709. doi: 10.1126/science.adv2684.
Joseph E Klebba 1 Nilotpal Roy 1 Steffen M Bernard 1 Stephanie Grabow 1 Melissa A Hoffman 1 Hui Miao 1 Junko Tamiya 1 Jinwei Wang 1 Cynthia Berry 1 Antonio Esparza-Oros 1 Richard Lin 1 Yongsheng Liu 1 Marie Pariollaud 1 Holly Parker 1 Igor Mochalkin 1 Sareena Rana 2 Aaron N Snead 1 Eric J Walton 1 Taylor E Wyrick 1 Erick Aitichson 1 Karl Bedke 1 Jacyln C Brannon Joel M Chick Kenneth Hee Benjamin D Horning 1 Mohamed Ismail 2 Kelsey N Lamb 1 Wei Lin 1 Justine Lu 1 Martha K Pastuszka 1 Jonathan Pollock 1 John J Sigler 1 Mona Tomaschko 2 Eileen Tran Chanyu Yue 1 Todd M Kinsella Miriam Molina-Arcas 2 Brian N Cook 1 Gabriel M Simon 1 David S Weinstein 1 Julian Downward 2 Matthew P Patricelli 1
Affiliations

Affiliations

  • 1 Vividion Therapeutics, 5820 Nancy Ridge Drive, San Diego, CA, USA.
  • 2 Francis Crick Institute, 1 Midland Road, London, UK.
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.

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