A neomorphic protein interface catalyzes covalent inhibition of RASG12D aspartic acid in tumors.
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).
Authors
Weller Weller, Burnett Burnett, Jiang Jiang, Chakraborty Chakraborty, Zhang Zhang, Vita Vita, Dilly Dilly, Kim Kim, Maldonato Maldonato, Seamon Seamon, Eilerts Eilerts, Milin Milin, Marquez Marquez, Spradlin Spradlin, Helland Helland, Gould Gould, Ziv Ziv, Dinh Dinh, Steele Steele, Wang Wang, Mu Mu, Chugh Chugh, Feng Feng, Hennessey Hennessey, Wang Wang, Roth Roth, Rees Rees, Ronan Ronan, Wolpin Wolpin, Hahn Hahn, Holderfield Holderfield, Wang Wang, Koltun Koltun, Singh Singh, Gill Gill, Smith Smith, Aguirre Aguirre, Jiang Jiang, Knox Knox, Wildes Wildes
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