Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS
成果类型：
Article
署名作者：
Schulze, Christopher J.; Seamon, Kyle J.; Zhao, Yulei; Yang, Yu C.; Cregg, Jim; Kim, Dongsung; Tomlinson, Aidan; Choy, Tiffany J.; Wang, Zhican; Sang, Ben; Pourfarjam, Yasin; Lucas, Jessica; Cuevas-Navarro, Antonio; Ayala-Santos, Carlos; Vides, Alberto; Li, Chuanchuan; Marquez, Abby; Zhong, Mengqi; Vemulapalli, Vidyasiri; Weller, Caroline; Gould, Andrea; Whalen, Daniel M.; Salvador, Anthony; Milin, Anthony; Saldajeno-Concar, Mae; Dinglasan, Nuntana; Chen, Anqi; Evans, Jim; Knox, John E.; Koltun, Elena S.; Singh, Mallika; Nichols, Robert; Wildes, David; Gill, Adrian L.; Smith, Jacqueline A. M.; Lito, Piro
署名单位：
Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine
刊物名称：
SCIENCE
ISSN/ISSBN：
0036-9035
DOI：
10.1126/science.adg9652
发表日期：
2023-08-18
页码：
794-799
关键词：
kras(g12c) inhibition
cyclosporine-a
ras oncogenes
cyclophilin
binding
calcineurin
resistance
摘要：
The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRAS(G12C) (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRAS(G12C) tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRAS(G12C) or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).