KRAS is vulnerable to reversible switch-II pocket engagement in cells

Vasta, J. D.; Peacock, D. M.; Zheng, Q.; Walker, J. A.; Zhang, Z.; Zimprich, C. A.; Thomas, M. R.; Beck, M. T.; Binkowski, B. F.; Corona, C. R.; Robers, M. B.; Shokat, K. M.

doi:10.1101/2021.10.15.464544

bioRxiv · 10.1101/2021.10.15.464544

KRAS is vulnerable to reversible switch-II pocket engagement in cells

Vasta, J. D.·Peacock, D. M.·Zheng, Q.·Walker, J. A.·Zhang, Z.·Zimprich, C. A.·Thomas, M. R.·Beck, M. T.·Binkowski, B. F.·Corona, C. R.·Robers, M. B.·Shokat, K. M.

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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.

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Vasta, J. D., Peacock, D. M., Zheng, Q., Walker, J. A., Zhang, Z., Zimprich, C. A., Thomas, M. R., Beck, M. T., Binkowski, B. F., Corona, C. R., Robers, M. B., Shokat, K. M.. 2021-10-15. KRAS is vulnerable to reversible switch-II pocket engagement in cells. https://doi.org/10.1101/2021.10.15.464544

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