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

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

Momelotinib inhibits the proliferation of parental Ba/F3 cells (Ba/F3-wt) stimulated by IL-3 (IC50: 1400 nM) and it also inhibits PI3K/AKT and Ras/MAPK signaling induced by IL-6 and IGF-1. Momelotinib inhibits erythroid colony growth in vitro from JAK2V617F-positive PV patients with similar potency (IC50: 2 μM-4 μM) [1]. Momelotinib causes the inhibition of cell proliferation in cell lines constitutively activated by JAK2 or MPL signaling, including Ba/F3-MPLW515L cells, Ba/F3-TEL-JAK2 cells and CHRF-288-11 cells (IC50: 200 nM, 1 nM and 700 nM, respectively) and it also induces apoptosis as a single agent and synergizes with the conventional anti-MM therapies bortezomib and melphalan in primary multiple myeloma (MM) cells [2].

Momelotinib normalizes white cell counts, spleen size, hematocrit, in a murine MPN model. It also restores physiologic levels of inflammatory cytokines [3].