ZT-12-037-01 is a specific and ATP-competitive STK19 inhibitor with IC50s of 23.96 nM and 27.94 nM for STK19 (WT) and STK19 (D89N), respectively. It displays extremely high kinase selectivity using KINOMEscan against a panel of 468 diverse kinases using an in vitro ATP-site competition binding assay at 1 μM.
ZT-12-037-01 treatment efficiently inhibits phosphorylation of NRAS in a dose- and time-dependent manner. Furthermore, with increasing ATP concentrations, the IC50 of ZT-12-037-01 against STK19 accordingly increased, indicating that ZT-12-037-01 is an ATP-competitive inhibitor for STK19. ZT-12-037-01 treatment significantly inhibits mutant NRAS-STK19-driven melanocyte colony formation, proliferation, and tumor formation. Pro-apoptotic effect of ZT-12-037-01 is dramatically enhanced in cells expressing oncogenic NRAS[1].
ZT-12-037-01 is a highly potent STK19 inhibitor with low in vivo toxicity. Its treatment also inhibits growth of SK-MEL-2 xenograft melanoma (with NRASQ61R) in a dose-dependent manner[1].
[1] Yin C, et al. Cell. 2019, 176(5):1113-1127.