Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D

  • Nat Chem Biol. 2024 Mar 5. doi: 10.1038/s41589-024-01565-w.
Qinheng Zheng  #  1 ,  Ziyang Zhang  #  2  3 ,  Keelan Z Guiley  1 ,  Kevan M Shokat  4  5
Affiliations
  • 1. Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, USA.
  • 2. Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, USA. [email protected].
  • 3. Department of Chemistry, University of California, Berkeley, CA, USA. [email protected].
  • 4. Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, USA. [email protected].
  • 5. Department of Chemistry, University of California, Berkeley, CA, USA. [email protected].
  • # Contributed equally.
PMID: 38443470 DOI: 10.1038/s41589-024-01565-w
Abstract

K-Ras is the most commonly mutated oncogene in human Cancer. The recently approved non-small cell lung Cancer drugs sotorasib and adagrasib covalently capture an acquired cysteine in K-Ras-G12C mutation and lock it in a signaling-incompetent state. However, covalent inhibition of G12D, the most frequent K-Ras mutation particularly prevalent in pancreatic ductal adenocarcinoma, has remained elusive due to the lack of aspartate-targeting chemistry. Here we present a set of malolactone-based electrophiles that exploit ring strain to crosslink K-Ras-G12D at the mutant aspartate to form stable covalent complexes. Structural insights from X-ray crystallography and exploitation of the stereoelectronic requirements for attack of the electrophile allowed development of a substituted malolactone that resisted attack by aqueous buffer but rapidly crosslinked with the aspartate-12 of K-Ras in both GDP and GTP state. The GTP-state targeting allowed effective suppression of downstream signaling, and selective inhibition of K-Ras-G12D-driven Cancer cell proliferation in vitro and xenograft growth in mice.

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