A neomorphic protein interface catalyzes covalent inhibition of RASG12D aspartic acid in tumors

  • Science. 2025 Jul 24;389(6758):eads0239. doi: 10.1126/science.ads0239.
Caroline Weller  #  1 ,  G Leslie Burnett  #  1 ,  Lingyan Jiang  #  1 ,  Sujata Chakraborty  1 ,  Dongyu Zhang  1 ,  Nicole A Vita  1 ,  Julien Dilly  2 ,  Eejung Kim  2 ,  Benjamin Maldonato  1 ,  Kyle Seamon  1 ,  Diane F Eilerts  1 ,  Anthony Milin  1 ,  Abby Marquez  1 ,  Jessica Spradlin  1 ,  Ciara Helland  1 ,  Andrea Gould  1 ,  Tamar Bar Ziv  1 ,  Phuong Dinh  1 ,  Shelby L Steele  1 ,  Zhican Wang  1 ,  Yunming Mu  1 ,  Seema Chugh  2 ,  Hanrong Feng  2 ,  Conner Hennessey  2 ,  Junning Wang  2 ,  Jennifer Roth  3 ,  Matthew Rees  3 ,  Melissa Ronan  3 ,  Brian M Wolpin  2 ,  William C Hahn  2 ,  Matthew Holderfield  1 ,  Zhengping Wang  1 ,  Elena S Koltun  1 ,  Mallika Singh  1 ,  Adrian L Gill  1 ,  Jacqueline A M Smith  1 ,  Andrew J Aguirre  2  3 ,  Jingjing Jiang  1 ,  John E Knox  1 ,  David Wildes  1
Affiliations
  • 1. Revolution Medicines, Inc., Redwood City, CA, USA.
  • 2. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • 3. Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • # Contributed equally.
PMID: 40705880 DOI: 10.1126/science.ads0239
Abstract

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 RasG12D 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 KRASG12D cancers, including the investigational agent zoldonrasib (RMC-9805) currently undergoing clinical evaluation (NCT06040541).