Activating mutations in NRAS account for 20%-30% of melanoma. but, there are no effective anti-NRAS therapies. Originally, it reports that the serine/threonine-protein kinase 19 (STK19) phosphorylate a-casein at serine/threonine residues and histones at serine residues. However, the role of STK19 in cancer initiation and development is poorly appreciated. Importantly, STK19 harbors significant somatic hotspot mutations in 5% of melanoma and 10% of skin basal cell carcinoma respectively. It is the top melanoma driver genes. This strong genetic evidence implies an important, but uncharacterized role of STK19 in melanocyte malignant transformation and melanoma progression. Here, the authors identify a previously uncharacterized serine/threonine kinase STK19 as a NRAS activator. Meanwhile, they develop ZT-12-037-01 is a specific and ATP-competitive STK19 inhibitor.
ZT-12-037-01 is a specific and ATP-competitive STK19 inhibitor.
ZT-12-037-01 has a potent inhibitory activity against STK19 with an IC50 of 24.04 nM. However, it remarkably decreases inhibitory activity toward the G9a histone lysine methyltransferase with an IC50 of 467.4 nM. ZT-12-037-01 treatment efficiently inhibits phosphorylation of NRAS in a dose- and time-dependent manner. In addition, ZT-12-037-01 has similar IC50 for STK19WT and STK19D89N (23.96 nM and 27.94 nM, respectively).
ZT-12-037-01 significantly inhibits mutant NRAS-STK19-driven melanocyte colony formation, proliferation, and tumor formation. Meanwhile, ZT-12-037-01 also inhibits growth of SK-MEL-2 xenograft melanoma in a dose-dependent manner. It effectively inhibits cell proliferation and induced apoptosis of SK-MEL-2 tumors. Moreover, ZT-12-037-01 significantly prolongs the survival of recipients in SK-MEL-2 xenograft tumor-bearing mice. It inhibits NRAS activity in a dose-dependent manner but did not affect the levels of H3K9 methylation, a downstream marker of G9a activity. Thus, pro-apoptotic effect of ZT-12-037-01 is dramatically enhances in cells expressing oncogenic NRAS.
All in all, ZT-12-037-01 is a specific STK19 inhibitor. It effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth. ZT-12-037-01 might overcome or prevent drug-resistance in patients with RAS mutation cancers in future preclinical and ultimately clinical studies.