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Preprint WatchModerateOctober 14th, 2026

KRAS recognition by Src: Mechanistic insights from Molecular Dynamics Simulations

Lu, H.; Xu, H.; Marti, J.; Ma, B.; FARAUDO, J.

Molecular dynamics simulations describe how c-Src recognises KRas in both GTP-bound and GDP-bound states, proposing a structural basis for Src-mediated phosphorylation of Ras independent of nucleotide state.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This is a simulation study rather than a therapeutic test, and its claim is that c-Src engages KRas in both nucleotide states. That matters for drug design because most KRAS inhibitors are nucleotide-state selective. Claidex holds two KRAS failures that were not efficacy verdicts. In bgb-53038-kras-solid-tumors-phase1-strategic-reprioritization the programme was reprioritised before an efficacy readout, and sotorasib-durvalumab-kras-g12c-ctdna-stage3-nsclc-phase2-enrollment-collapse ended on enrollment rather than on activity. Neither closes the question the preprint raises. A state-independent interaction partner would predict escape routes that state-selective inhibitors do not cover, which is a hypothesis for preclinical resistance work rather than a near-term clinical design change.

Abstract excerpt

c-Src, the first identified oncogene, and Ras, one of the most frequently mutated proteins in human cancers, can activate each other to promote tumorigenesis. Recent experimental work has found that c-Src can recognize and phosphorylate both GTP-bound and GDP-bound forms of KRas, as well as GTP-bound NRas and GDP-bound HRas. The molecular mechanisms underlying this specific recognition remain unknown. We leverage molecular simulation tools (eg. Molecular dynamics and Markov State Models analysis) to model a Src-KRas interaction in solution to identify the mechanisms underlying the c-Src recognition of the G12D mutant of KRas4B-G12D, the most prevalent in humans. We found that the most populated states of nucleotide-bound KRas maintain more open and dynamic switch regions, facilitating easier access of c-Src to the phosphorylation sites of KRas (Tyr32 for GTP-bound KRas and Tyr64 for GDP-bound KRas). We further identify two c-Src specific regions (residues 340-359 and 453-473), along with putative recognition hotspots at Leu347, Asp348, Lys351, Gly459, Arg460, and Val461, that may contribute to the stabilization of phosphorylation-competent KRas conformations. c-Src selectively recognizes and engages specific macrostates of KRas, which may constitute privileged targets for the rational design of peptide-based inhibitors.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.