2. Academic Validation
  3. Targeting KRASG13C with cyclic linker based inhibitors to explore warhead orientation

Targeting KRASG13C with cyclic linker based inhibitors to explore warhead orientation

  • Sci Rep. 2025 Oct 31;15(1):38213. doi: 10.1038/s41598-025-22145-5.
Tonia Kirschner 1,  João Rodriguez 2,  Emerson Gonçalves Moreira 2,  Janina Niggenaber 1,  Jonas D Warmuth 1,  Hugo Verli 3,  Matthias P Müller 4,  Daniel Rauh 5
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, Drug Discovery Hub Dortmund (DDHD), TU Dortmund University, Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
  • 2 Programa de Pos-Graduacao em Biologia Celular e Molecular (PPGBCM), Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Av. Bento Goncalves, Porto Alegre, 9500, CEP 91501-970, RS, Brazil.
  • 3 Programa de Pos-Graduacao em Biologia Celular e Molecular (PPGBCM), Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Av. Bento Goncalves, Porto Alegre, 9500, CEP 91501-970, RS, Brazil. [email protected].
  • 4 Department of Chemistry and Chemical Biology, Drug Discovery Hub Dortmund (DDHD), TU Dortmund University, Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany. [email protected].
  • 5 Department of Chemistry and Chemical Biology, Drug Discovery Hub Dortmund (DDHD), TU Dortmund University, Zentrum für Integrierte Wirkstoffforschung (ZIW), Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany. [email protected].
PMID: 41174214 DOI: 10.1038/s41598-025-22145-5
Abstract

The small GTPase KRAS is a key driver of carcinogenesis when mutated, and significant progress has been made in targeting KRASG12C and Other oncogenic variants. Building on our previous work demonstrating the potential of nucleotide-based inhibitors with an acrylamide warhead to target KRASG13C, we designed and synthesized a library of nucleotide-based compounds with cyclic linkers to explore the effect of warhead orientation on reactivity toward Cys13. Using mass spectrometry, kinetic studies, and protein X-ray crystallography, we validated the binding and reactivity of these modulators. In addition, computational predictions of the conformational space of the linkers and warheads provided insights into their reactivity, which agreed well with the experimental data. These findings advance our understanding of the structure-reactivity relationship in these nucleotide-based KRAS inhibitors and will be the basis for further optimization.

Keywords

Computer-aided drug design; G13C; KRAS; Nucleotide-based inhibitors.

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