ZT-12-037-01

Biological Activity

ZT-12-037-01 is a potent, selective, ATP-competitive STK19 inhibitor with IC50 values of 23.96 nM and 27.94 nM for STK19 (WT) and STK19 (D89N), respectively. ZT-12-037-01 effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. ZT-12-037-01 (3 μM; 14 days) significantly inhibits mutant NRAS-STK19-driven melanocyte colony formation and proliferation. 

In vivo, ZT-12-037-01 (25-50 mg/kg; injection subcutaneously; once daily) 21 days treatment inhibits growth of SK-MEL-2 xenograft melanoma and the sections of tumors indicates induction of apoptosis by increasing cleaved caspase-3.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information

References

Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis
Chengqian Yin, et al. Cell. 2019 Feb 21;176(5):1113-1127.e16. PMID: 30712867.