Kinome profiling enabled development of a LATS1/2 inhibitor with wound healing potential.

NCGC-6782, a LATS1/2 inhibitor discovered from profiling 257 kinase inhibitors, robustly promotes YAP nuclear translocation and proproliferative signaling in wound-healing models.

• Why it matters: System-level mapping of kinase inhibitor polypharmacology can reveal repurposing opportunities and new starting points, but LATS1/2-targeted wound-healing agents remained to be optimized.
• What they did: The team profiled 257 kinase inhibitors to define promiscuity and selectivity, then used scaffold hopping and property-based optimization from AT-7867 to develop NCGC-6782. They tested it in biochemical/cell assays, chemoproteomics/kinetics, and in vivo murine liver and full-thickness excisional skin injury models.
• The result: NCGC-6782 inhibited LATS1/2, reduced YAP phosphorylation, and in murine full-thickness excisional skin injury significantly shortened wound-closure time without systemic toxicity, with YAP-dependent gene upregulation at 4 h and cell-cycle activation at 24 h.

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