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Targeting KRASG13C with cyclic linker based inhibitors to explore warhead orientation
Tonia Kirschner1, João Rodriguez2, Emerson Gonçalves Moreira2
1Department 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.
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.
Insights
Researchers developed novel nucleotide-based KRAS inhibitors targeting KRASG13C. Cyclic linkers optimized warhead orientation, enhancing reactivity and providing insights for future drug design against KRAS-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Mutated KRAS is a critical driver of carcinogenesis.
- Targeting oncogenic KRAS variants like KRASG12C has shown promise.
- Previous work established nucleotide-based inhibitors with acrylamide warheads for KRASG13C.
Purpose of the Study:
- To design and synthesize novel nucleotide-based compounds with cyclic linkers.
- To investigate the impact of warhead orientation on reactivity toward Cys13.
- To explore structure-reactivity relationships for KRAS inhibitors.
Main Methods:
- Synthesis of a library of nucleotide-based compounds with cyclic linkers.
- Validation using mass spectrometry, kinetic studies, and protein X-ray crystallography.
- Computational predictions of linker and warhead conformational space.
Main Results:
- Validated binding and reactivity of the designed KRAS modulators.
- Experimental data aligned well with computational predictions.
- Demonstrated the influence of linker design on warhead reactivity.
Conclusions:
- The study advances understanding of structure-reactivity relationships in KRAS inhibitors.
- Findings provide a basis for further optimization of nucleotide-based KRAS inhibitors.
- Cyclic linkers are effective in modulating warhead orientation and reactivity.
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