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<p>The small GTPase KRAS is a key driver of carcinogenesis when mutated, and significant progress has been made in targeting KRAS<sup>G12C</sup> and other oncogenic variants. Building on our previous work demonstrating the potential of nucleotide-based inhibitors with an acrylamide warhead to target KRAS<sup>G13C</sup>, 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.</p>

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Targeting KRASG13C with cyclic linker based inhibitors to explore warhead orientation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月31日

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  • Tonia Kirschner,
  • João Rodriguez,
  • Emerson Gonçalves Moreira,
  • Janina Niggenaber,
  • Jonas D. Warmuth,
  • Hugo Verli,
  • Matthias P. Müller,
  • Daniel Rauh

摘要

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.