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, Metzger Justine, Pastuszka Martha K, Pollock Jonathan, Sigler John J, Tomaschko Mona, Tran Eileen, Kinsella Todd M, Molina-Arcas Miriam, Simon Gabriel M, Weinstein David S, Downward Julian, Patricelli Matthew P
bioRxiv. 2024 Dec 20:2024.12.17.629001. doi: 10.1101/2024.12.17.629001.
Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3K's role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block the ability of RAS to activate PI3K activity. These inhibitors have a profound impact on the growth of RAS mutant and also HER2 over-expressing tumors, particularly when combined with other inhibitors of the RAS/MAPK pathway, without causing hyperglycemia.
对磷脂酰肌醇-3激酶（PI3K）的RAS结合结构域（RBD）进行基因破坏可阻止突变型RAS驱动的肿瘤在小鼠体内生长，且不影响PI3K在胰岛素介导的葡萄糖稳态控制中的作用。选择性阻断RAS-PI3K相互作用可能是治疗RAS依赖性癌症的一种有吸引力的策略，因为它可以避免与PI3K脂质激酶活性抑制剂（如阿培利司）相关的毒性。在此，我们报告了可与PI3K p110α的RBD中的半胱氨酸242共价结合并阻断RAS激活PI3K活性能力的化合物。这些抑制剂对RAS突变型肿瘤以及HER2过表达肿瘤的生长有深远影响，特别是与RAS/MAPK途径的其他抑制剂联合使用时，且不会导致高血糖。
