KRAS is vulnerable to reversible switch-II pocket engagement in cells
KRAS is vulnerable to reversible switch-II pocket engagement in cells
Abstract Current small molecule inhibitors of KRAS(G12C) bind irreversibly in the switch-II pocket, exploiting the strong nucleophilicity of the acquired cysteine as well as the preponderance of the GDP-bound form of this mutant. Nevertheless, many oncogenic KRAS mutants lack these two features, and it remains unknown whether targeting the switch-II pocket is a practical therapeutic approach for KRAS mutants beyond G12C. Here we use NMR spectroscopy and a novel cellular KRAS engagement assay to address this question by examining a collection of SII-P ligands from the literature and from our own laboratory. We show that the switch-II pockets of many GTP hydrolysis-deficient KRAS hotspot (G12, G13, Q61) mutants are accessible using non-covalent ligands, and that this accessibility is not necessarily coupled to the GDP state of KRAS. The results we describe here emphasize the switch-II pocket as a privileged drug binding site on KRAS and unveil new therapeutic opportunities in RAS-driven cancer.
Peacock D. Matthew、Walker Joel A.、Binkowski Brock F.、Vasta James D.、Zimprich Chad A.、Thomas Morgan R.、Zheng Qinheng、Zhang Ziyang、Robers Matthew B.、Beck Michael T.、Shokat Kevan M.、Corona Cesear R.
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California San FranciscoPromega Corporation. 2800 Woods Hollow RoadPromega Corporation. 2800 Woods Hollow RoadPromega Corporation. 2800 Woods Hollow RoadPromega Corporation. 2800 Woods Hollow RoadPromega Corporation. 2800 Woods Hollow RoadDepartment of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California San FranciscoDepartment of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California San FranciscoPromega Corporation. 2800 Woods Hollow RoadPromega Corporation. 2800 Woods Hollow RoadDepartment of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California San FranciscoPromega Corporation. 2800 Woods Hollow Road
基础医学分子生物学肿瘤学
Peacock D. Matthew,Walker Joel A.,Binkowski Brock F.,Vasta James D.,Zimprich Chad A.,Thomas Morgan R.,Zheng Qinheng,Zhang Ziyang,Robers Matthew B.,Beck Michael T.,Shokat Kevan M.,Corona Cesear R..KRAS is vulnerable to reversible switch-II pocket engagement in cells[EB/OL].(2025-03-28)[2025-05-01].https://www.biorxiv.org/content/10.1101/2021.10.15.464544.点此复制
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