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

Autor: Schulze CJ; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Seamon KJ; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Zhao Y; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA., Yang YC; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Cregg J; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Kim D; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA., Tomlinson A; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Choy TJ; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Wang Z; Department of Non-clinical Development and Clinical Pharmacology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Sang B; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA., Pourfarjam Y; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA., Lucas J; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA., Cuevas-Navarro A; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA., Ayala-Santos C; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA., Vides A; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA., Li C; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA., Marquez A; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Zhong M; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Vemulapalli V; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Weller C; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Gould A; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Whalen DM; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Salvador A; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Milin A; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Saldajeno-Concar M; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Dinglasan N; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Chen A; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Evans J; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Knox JE; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Koltun ES; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Singh M; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Nichols R; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Wildes D; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Gill AL; Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Smith JAM; Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA., Lito P; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2023 Aug 18; Vol. 381 (6659), pp. 794-799. Date of Electronic Publication: 2023 Aug 17.
DOI: 10.1126/science.adg9652
Abstrakt: 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).
Databáze: MEDLINE
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