The serine/threonine-protein kinase 19 (STK19) is a critical regulator of NRAS, one of the major isoforms of the RAS family. The oncogenic mutation of NRAS is a critical driver for the proliferation of melanocyte and eventually the transformation to melanoma. ZT-12-037-01 is a potent and selective STK19 inhibitor with an IC50 value of 24.04nM. ZT-12-037-01 at the doses of 0.01–3μM efficiently inhibited the phosphorylation of NRAS in vitro at a dose- and time-dependent manner. It also showed STK19-targeted inhibition in the presence of ATP (10, 30, 100, and 300μM) with increasing IC50 values (35.46, 95.6, 169.3 and 680.7nM, respectively).
The inhibitory effect of ZT-12-037-01 (0.1–3μM) on STK19WT and STK19D89N-activated NRAS phosphorylation was observed in human primary melanocytes. Treatment with 3μM ZT-12-037-01 significantly suppressed NRAS-STK19-driven colony formation in mutant melanocytes. In nude mice inoculated with SK-MEL-2 cells, ZT-12-037-01 treatment (at 25 and 50mg/kg) inhibited tumor growth in a dose-dependent manner. Mice treated by ZT-12-037-01 also presented a markedly lower level of Ki67 and a higher expression of cleaved caspase-3 in tumors. The survival rate of SK-MEL-2 xenografts showed significantly prolonged survival rate compared with control group[1].
作用机制
ZT-12-037-01 is an ATP-competitive inhibitor for STK19[1].
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