Momelotinib sulfate is an ATP-competitive JAK1/JAK2 inhibitor (IC50: 11 nM/18 nM). It has 10-fold selectivity versus JAK3.

JAK2:18 nM, JAK1:11 nM, JAK3:155 nM

Momelotinib sulfate inhibits growth of Ba/F3-JAK2V617F and Ba/F3-MPLW515L cells (IC50: 200 nM) or human erythroleukemia (HEL) cells (IC50: 1.5 μM). However, it has considerably less activity against BCR-ABL harboring K562 cells (IC50=58 μM) and FLT3 mutation harboring MV4-11 cells (IC50: 3 μM). Proliferation of parental Ba/F3 cells (Ba/F3-wt) stimulated with IL-3 is inhibited (IC50: 1.4 μM). This is same as the established role of IL-3-dependent signaling in the parental cell line [1].

Administering Momelotinib sulfate at doses of 50 and 100 mg/kg had minimal impact on peripheral blood counts over 8 weeks. The median peak plasma concentrations reached 7.1 μM and 32.1μM for the lower and higher doses, respectively, with a 2-hour half-life. Trough levels were observed at 10nM (25 mg/kg) and 900nM (50 mg/kg) 12 hours post-administration. The compound demonstrated high plasma concentrations after oral intake (Cmax= 40.4 μM; Tmax=4 h), suggesting high oral bioavailability. This is likely due to its low blood clearance rate (6.3 mL/min/kg), indicating reduced hepatic first-pass metabolism. In a study, by day 34 post-transplantation, white blood cell counts and hematocrit values in Balb/c mice exceeded the normal range by more than one standard deviation (SD). Subsequent treatment with 25 mg/kg or 50 mg/kg Momelotinib sulfate, or a vehicle control, initiated a rapid decrease in white cell counts within six days and a decrease in hematocrit after 20 days, showing the drug's efficacy in modulating hematologic parameters.