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

• 成果类型: Article
• 署名作者: Klebba, Joseph E.; Roy, Nilotpal; Bernard, Steffen M.; Grabow, Stephanie; Hoffman, Melissa A.; Miao, Hui; Tamiya, Junko; Wang, Jinwei; Berry, Cynthia; Esparza-Oros, Antonio; Lin, Richard; Liu, Yongsheng; Pariollaud, Marie; Parker, Holly; Mochalkin, Igor; Rana, Sareena; Snead, Aaron N.; Walton, Eric J.; Wyrick, Taylor E.; Aitichson, Erick; Bedke, Karl; Brannon, Jacyln C.; Chick, Joel M.; Hee, Kenneth; Horning, Benjamin D.; Ismail, Mohamed; Lamb, Kelsey N.; Lin, Wei; Lu, Justine; Pastuszka, Martha K.; Pollock, Jonathan; Sigler, John J.; Tomaschko, Mona; Tran, Eileen; Yue, Chanyu; Kinsella, Todd M.; Molina-Arcas, Miriam; Cook, Brian N.; Simon, Gabriel M.; Weinstein, David S.; Downward, Julian; Patricelli, Matthew P.
• 署名单位: Francis Crick Institute; Novartis; Novartis USA
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adv2684
• 发表日期: 2025-11-13
• 页码: 702-709
• 关键词: PHOSPHOINOSITIDE 3-KINASE; p110-alpha; pi3k

摘要

Genetic disruption of the RAS binding domain (RBD) of phosphoinositide 3-kinase alpha (PI3K alpha) impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not affect PI3K alpha's role in insulin-mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K alpha interaction may represent a strategy for treating RAS-dependent cancers as it avoids the toxicity associated with inhibitors of PI3K alpha lipid kinase activity. We developed compounds that bind covalently to cysteine 242 in the RBD of PI3K p110 alpha and block RAS activation of PI3K alpha 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.