NCGC-023 (NCGC00846023) is a potent, selective small-molecule inhibitor of LATS1/2 with IC50 of 14.1 nM and 14.7 nM for LATS1 and LATS2, respectively, effectively activates Yap protein in vitro and in vivo.
NCGC-023 shows robust LATS1/2 inhibition in cell-based NanoBRET target-engagement assays (IC50 = 367 nM and 57 nM for LATS1 and LATS2, respectively.
caused significant induction of transcriptional targets of Yap1, including Amotl2, Ctgf, and Cyr61 in HepG2 human hepatocellular carcinoma cells.
NCGC-023 (acute intraperitoneal (IP)) markedly inhibited Yap Ser397 phosphorylation in mouse livers up to 8 hours after treatment.
NCGC-023 protects human enteroids from radiation in vitro.
NCGC-023 treatment before IR upregulated key signaling pathways controlled by LATS1/2, including Yap-dependent regenerative responses involving Il-33 and Yap-independent cellular responses to heavy metals mediated by metallothioneins.