Kinome-profiling enabled discovery of a LATS1/2 inhibitor with wound healing potential

ABSTRACT: System-level mapping of kinase inhibitors polypharmacology can uncover opportunities for drug repurposing and identify starting points for medicinal chemistry campaigns aimed at novel targets. Here, we describe a large-scale profiling of 257 kinase inhibitors that revealed domains of promiscuity, pockets of selectivity and a broad region of uninhibited targets. Focusing on a subcluster enriched for AGC group kinases and using the AKT inhibitor AT-7867 (an antiproliferative agent) as a starting point, we employed scaffold hopping and property-based optimization to discover NCGC-6782, a LATS1/2 inhibitor with robust pro-proliferative activity. In cells, NCGC-6782 inhibited LATS1/2 activity, promoted rapid YAP nuclear translocation and transactivation of YAP-target genes. Kinome-wide profilings demonstrated good in vitro selectivity and exquisite chemoproteomic and kinetic selectivity. Transcriptomics and proteomics following NCGC-6782 revealed upregulation of YAP-dependent genes (4h) followed by activation of cell-cycle programs (24h). Consistently, NCGC-6782 accelerated proliferative regeneration in both cell-based and in vivo wound healing models

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Dingyin Tao  

LAB HEAD: Dingyin Tao

PROVIDER: PXD073488 | Pride | 2026-07-15

REPOSITORIES: Pride