What is the target of molotinib/mometinib?

Momelotinib is an ATP-competitive small molecule that inhibits JAK1 (half maximum inhibitory concentration [IC50]=11nM), JAK2 (IC50=18nM), JAK3 (IC50=155nM) and TYK2 (IC50=17nM) and other kinases. The drug is administered orally in tablet form, and the 200 mg dose provides plasma exposure in healthy subjects similar to the 300 mg capsule formulation; the effects of food or omeprazole are not considered clinically significant.

Additional pharmacokinetic and safety studies indicate that dose adjustment of molotinib may not be necessary in patients with renal impairment or mild to moderate hepatic impairment, but a dose reduction is recommended in patients with severe hepatic impairment. In vitro tests show that molotinib can inhibit the growth of Ba/F3-JAK2V617F and human erythroleukemia (HEL) cells (IC50=1500nM) and Ba/F3-MPLW515L cells (IC50=200nM), but does not inhibit the growth of BCR Cell lines carrying mutant JAK2 were more efficiently inhibited than cell lines carrying mutant JAK3 alleles, and STAT-5 phosphorylation was inhibited in HEL cells with an IC50 of 400 nM.

Molotinib selectively inhibits the in vitro growth of JAK2V617F-carrying erythrocyte colonies from polycythemia patients and induces growth inhibition and apoptosis in JAK2-dependent hematopoietic cell lines. In a murine model of MPN, molotinib normalized blood cell counts and spleen size and suppressed levels of inflammatory cytokines. Other targets of molotinib include CDK 2/cyclin A, MAPK8 (JNK1), PRKCN (PKD3), PRKD1 (PKCμ), ROCK2, TBK1, FLT3-ITD, and ACVR1.