# Targeting KRASG13C with cyclic linker based inhibitors to explore warhead orientation

## TL;DR

Researchers designed and tested new inhibitors to target a specific mutated form of the KRAS protein, focusing on how the structure of the inhibitors affects their reactivity.

## Contribution

The study introduces cyclic linker-based inhibitors to explore warhead orientation effects on KRASG13C reactivity.

## Key findings

- Cyclic linker-based inhibitors showed binding and reactivity toward Cys13 in KRASG13C.
- Computational predictions aligned with experimental data on inhibitor conformation and reactivity.
- The findings enhance understanding of structure-reactivity relationships in KRAS inhibitors.

## 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.

The online version contains supplementary material available at 10.1038/s41598-025-22145-5.