Targeting KRAS^G13C with cyclic linker based inhibitors to explore warhead orientation.

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Mutated KRAS is a critical driver of carcinogenesis.
• Targeting oncogenic KRAS variants like KRAS^G12C has shown promise.
• Previous work established nucleotide-based inhibitors with acrylamide warheads for KRAS^G13C.

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.