Single-atom inhibition of oncogenic drivers through cysteine coordination

Conventional small-molecule inhibitors rely on molecular recognition within suitable binding pockets, leaving many disease-associated proteins difficult to target. This study introduces a single-atom inhibitor concept in which gold (Au) engages critical cysteine residues of oncogenic drivers to suppress their activity.

The authors used an AI-assisted few-shot learning approach to identify an EGFR-targeting peptide, 10714, for in vivo Au delivery. The lead candidate promoted Au accumulation in EGFR-expressing cells and tumors. In vivo, Au exploited its intrinsic affinity for cysteine to inhibit two structurally distinct oncogenic proteins: EGFR T790M via Cys797 and KRAS G12C via mutation-derived Cys12, both adjacent to their respective nucleotide-binding pockets. Structural and computational analyses supported stabilization of inactive nucleotide-bound states, and mutation of these cysteine residues abrogated Au-mediated inhibition.

10714-Au consequently suppressed oncogenic signaling, reduced non-small-cell lung cancer cell viability, and inhibited tumor growth in EGFR- and KRAS-mutant xenograft models and patient-derived organoids.

These findings establish proof of principle for single-atom inhibition across structurally distinct oncogenic drivers and suggest that localized atomic coordination could provide an alternative mode of target engagement to conventional pocket-dependent inhibition.