2. Academic Validation
  3. Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D

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

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. ziyang@berkeley.edu.
  • 3 Department of Chemistry, University of California, Berkeley, CA, USA. ziyang@berkeley.edu.
  • 4 Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, USA. kevan.shokat@ucsf.edu.
  • 5 Department of Chemistry, University of California, Berkeley, CA, USA. kevan.shokat@ucsf.edu.
  • # 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.

Figures
Products