课题组开发了在PI3K p110α RBD中与半胱氨酸242共价结合的化合物，并阻断RAS对PI3Kα活性的激活。在小鼠中，抑制剂可以减缓RAS突变肿瘤和人表皮生长因子受体2 （HER2）过表达肿瘤的生长，特别是当与RAS/丝裂原激活蛋白激酶途径的其他抑制剂联合使用时，而不会引起高血糖。
研究人员表示，磷酸肌肽3-激酶α (PI3Kα) RAS结合域（RBD）的遗传破坏会损害小鼠小鸟苷三磷酸酶RAS驱动的肿瘤生长，但不会影响PI3Kα在胰岛素介导的葡萄糖稳态控制中的作用。选择性阻断RAS-PI3Kα相互作用可能是治疗RAS依赖性癌症的一种策略，因为它可以避免与PI3Kα脂质激酶活性抑制剂相关的毒性。
附：英文原文
Title: Covalent inhibitors of the PI3Kα RAS binding domain impair tumor growth driven by RAS and HER2
Author: 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 Lin, Yongsheng Liu, Marie Pariollaud, Holly Parker, Igor Mochalkin, Sareena Rana, Aaron N. Snead, Eric J. Walton, Taylor E. Wyrick, Erick Aitchison, Karl Bedke, Jacyln C. Brannon, Joel M. Chick, Kenneth Hee, Benjamin D. Horning, Mohamed Ismail, Kelsey N. Lamb, Wei Lin, Justine Metzger, Martha K. Pastuszka, Jonathan Pollock, John J. Sigler, Mona Tomaschko, Eileen Tran, Chanyu Yue, Todd M. Kinsella, Miriam Molina-Arcas, Brian N. Cook, Gabriel M. Simon, David S. Weinstein, Julian Downward, Matthew P. Patricelli
Issue&Volume: 2025-10-09
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 impact 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 would avoid 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 (HER2) overexpressing tumors, particularly when combined with other inhibitors of the RAS/Mitogen-activated protein kinase pathway, without causing hyperglycemia.
DOI: adv2684
Source: https://www.science.org/doi/10.1126/science.adv2684