Article
A neomorphic protein interface catalyzes covalent inhibition of RASG12D aspartic acid in tumors.
Science (New York, N.Y.) - 24 Jul 2025
Weller Caroline, Burnett G Leslie, Jiang Lingyan, Chakraborty Sujata, Zhang Dongyu, Vita Nicole A, Dilly Julien, Kim Eejung, Maldonato Benjamin, Seamon Kyle, Eilerts Diane F, Milin Anthony, Marquez Abby, Spradlin Jessica, Helland Ciara, Gould Andrea, Ziv Tamar Bar, Dinh Phuong, Steele Shelby L, Wang Zhican, Mu Yunming, Chugh Seema, Feng Hanrong, Hennessey Conner, Wang Junning, Roth Jennifer, Rees Matthew, Ronan Melissa, Wolpin Brian M, Hahn William C, Holderfield Matthew, Wang Zhengping, Koltun Elena S, Singh Mallika, Gill Adrian L, Smith Jacqueline A M, Aguirre Andrew J, Jiang Jingjing, Knox John E, Wildes David
Abstract excerpt
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...
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