Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS

被引：93

作者：

Schulze, Christopher J. ^{[1
]}

Seamon, Kyle J. ^{[1
]}

Zhao, Yulei ^{[2
]}

Yang, Yu C. ^{[1
]}

Cregg, Jim ^{[3
]}

Kim, Dongsung ^{[2
]}

Tomlinson, Aidan ^{[3
]}

Choy, Tiffany J. ^{[1
]}

Wang, Zhican ^{[4
]}

Sang, Ben ^{[2
]}

Pourfarjam, Yasin ^{[2
]}

Lucas, Jessica ^{[2
]}

Cuevas-Navarro, Antonio ^{[2
]}

Ayala-Santos, Carlos ^{[2
]}

Vides, Alberto ^{[2
]}

Li, Chuanchuan ^{[2
]}

Marquez, Abby ^{[3
]}

Zhong, Mengqi ^{[3
]}

Vemulapalli, Vidyasiri ^{[1
]}

Weller, Caroline ^{[1
]}

Gould, Andrea ^{[1
]}

Whalen, Daniel M. ^{[3
]}

Salvador, Anthony ^{[3
]}

Milin, Anthony ^{[3
]}

Saldajeno-Concar, Mae ^{[3
]}

Dinglasan, Nuntana ^{[1
]}

Chen, Anqi ^{[3
]}

Evans, Jim ^{[1
]}

Knox, John E. ^{[3
]}

Koltun, Elena S. ^{[3
]}

Singh, Mallika ^{[1
]}

Nichols, Robert ^{[1
]}

Wildes, David ^{[1
]}

Gill, Adrian L. ^{[3
]}

Smith, Jacqueline A. M. ^{[1
]}

Lito, Piro ^{[2
,5
,6
]}

机构：

[1] Revolut Med Inc, Dept Biol, Redwood City, CA 94063 USA

[2] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[3] Revolut Med Inc, Dept Discovery Chem, Redwood City, CA 94063 USA

[4] Revolut Med Inc, Dept Nonclin Dev & Clin Pharmacol, Redwood City, CA 94063 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[6] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA

来源：

SCIENCE | 2023年 / 381卷 / 6659期

基金：

美国国家卫生研究院;

关键词：

KRAS(G12C) INHIBITION; CYCLOSPORINE-A; RAS ONCOGENES; CYCLOPHILIN; BINDING; CALCINEURIN; RESISTANCE;

D O I：

10.1126/science.adg9652

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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).

引用

页码：794 / 799

页数：6

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