Weller Caroline, Burnett G Leslie, Jiang Lingyan, Chakraborty Sujata, Zhang Dongyu, Vita Nicole A, Dilly Julien, Kim Eejung, Maldonato Benjamin, Seamon Kyle, Eilerts Diane F, Milin Anthony, Marquez Abby, Spradlin Jessica, Helland Ciara, Gould Andrea, Ziv Tamar Bar, Dinh Phuong, Steele Shelby L, Wang Zhican, Mu Yunming, Chugh Seema, Feng Hanrong, Hennessey Conner, Wang Junning, Roth Jennifer, Rees Matthew, Ronan Melissa, Wolpin Brian M, Hahn William C, Holderfield Matthew, Wang Zhengping, Koltun Elena S, Singh Mallika, Gill Adrian L, Smith Jacqueline A M, Aguirre Andrew J, Jiang Jingjing, Knox John E, Wildes David
Revolution Medicines, Inc., Redwood City, CA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Science. 2025 Jul 24;389(6758):eads0239. doi: 10.1126/science.ads0239.
Mutant RAS proteins are among the most prevalent drivers of human cancer, and the glycine to aspartic acid mutation at codon 12 (G12D) is the most common variant. Mutation-selective covalent inhibitors spare RAS in healthy tissue and enable extended pharmacodynamic effect, but covalent targeting of RAS is hindered by low nucleophilicity and high proteomic abundance of carboxylic acids. We overcame these challenges with compounds that bind cyclophilin A (CYPA) to create a neomorphic protein-protein interface between CYPA and active RAS that enables selective, enzyme-like rate enhancement of the covalent reaction between D12 and electrophilic warheads with exceptionally low intrinsic reactivity. This approach yielded orally bioavailable compounds with marked antitumor activity in multiple preclinical models of KRAS cancers, including the investigational agent zoldonrasib (RMC-9805) currently undergoing clinical evaluation (NCT06040541).
突变型RAS蛋白是人类癌症中最常见的驱动因素之一，密码子12处的甘氨酸到天冬氨酸突变（G12D）是最常见的变体。突变选择性共价抑制剂可使健康组织中的RAS免受影响，并能延长药效学效应，但RAS的共价靶向受到羧酸的低亲核性和高蛋白组丰度的阻碍。我们通过与亲环素A（CYPA）结合的化合物克服了这些挑战，在CYPA和活性RAS之间创建了一个新形态的蛋白质-蛋白质界面，该界面能够以极低的固有反应性实现D12与亲电弹头之间共价反应的选择性、类似酶的速率增强。这种方法产生了口服生物利用度高的化合物，在多种KRAS癌症的临床前模型中具有显著的抗肿瘤活性，包括目前正在进行临床评估的研究药物佐尔东拉西布（RMC-9805，NCT06040541）。
