2. Academic Validation
  3. Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS

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

  • Science. 2023 Aug 18;381(6659):794-799. doi: 10.1126/science.adg9652.
Christopher J Schulze # 1,  Kyle J Seamon # 1,  Yulei Zhao # 2,  Yu C Yang 1,  Jim Cregg 3,  Dongsung Kim 2,  Aidan Tomlinson 3,  Tiffany J Choy 1,  Zhican Wang 4,  Ben Sang 2,  Yasin Pourfarjam 2,  Jessica Lucas 2,  Antonio Cuevas-Navarro 2,  Carlos Ayala-Santos 2,  Alberto Vides 2,  Chuanchuan Li 2,  Abby Marquez 3,  Mengqi Zhong 3,  Vidyasiri Vemulapalli 1,  Caroline Weller 1,  Andrea Gould 1,  Daniel M Whalen 3,  Anthony Salvador 3,  Anthony Milin 3,  Mae Saldajeno-Concar 3,  Nuntana Dinglasan 1,  Anqi Chen 3,  Jim Evans 1,  John E Knox 3,  Elena S Koltun 3,  Mallika Singh 1,  Robert Nichols 1,  David Wildes 1,  Adrian L Gill 3,  Jacqueline A M Smith 1,  Piro Lito 2 5 6
Affiliations

Affiliations

  • 1 Department of Biology, Revolution Medicines, Inc., Redwood City, CA 94063, USA.
  • 2 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA.
  • 3 Department of Discovery Chemistry, Revolution Medicines, Inc., Redwood City, CA 94063, USA.
  • 4 Department of Non-clinical Development and Clinical Pharmacology, Revolution Medicines, Inc., Redwood City, CA 94063, USA.
  • 5 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 6 Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
  • # Contributed equally.
PMID: 37590355 DOI: 10.1126/science.adg9652
Abstract

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 KRASG12C (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRASG12C 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 KRASG12C or multiple Ras mutants are in clinical trials now (NCT05462717 and NCT05379985).

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