2. Academic Validation
  3. KRAS is vulnerable to reversible switch-II pocket engagement in cells

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

  • Nat Chem Biol. 2022 Jun;18(6):596-604. doi: 10.1038/s41589-022-00985-w.
James D Vasta  # 1,  D Matthew Peacock  # 2,  Qinheng Zheng  # 2,  Joel A Walker 1,  Ziyang Zhang 2,  Chad A Zimprich 1,  Morgan R Thomas 1,  Michael T Beck 1,  Brock F Binkowski 1,  Cesear R Corona 1,  Matthew B Robers 3,  Kevan M Shokat 4
Affiliations

Affiliations

  • 1 Promega Corporation, Madison, WI, USA.
  • 2 Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA.
  • 3 Promega Corporation, Madison, WI, USA. [email protected].
  • 4 Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA. [email protected].
  • # Contributed equally.
PMID: 35314814 DOI: 10.1038/s41589-022-00985-w
Abstract

Current small-molecule inhibitors of KRAS(G12C) bind irreversibly in the switch-II pocket (SII-P), 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 SII-P is a practical therapeutic approach for KRAS mutants beyond G12C. Here we use NMR spectroscopy and a 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 SII-Ps of many KRAS hotspot (G12, G13, Q61) mutants are accessible using noncovalent ligands, and that this accessibility is not necessarily coupled to the GDP state of KRAS. The results we describe here emphasize the SII-P as a privileged drug-binding site on KRAS and unveil new therapeutic opportunities in RAS-driven Cancer.

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