Ruxolitinib (INCB018424) is a potent, selective and orally bioavailable inhibitor of JAK1 and JAK2 with IC₅₀ of 2.7 and 4.5 nM, respectively. It shows modest selectivity against Tyk2 (IC₅₀, 19 nM) and marked selectivity against JAK3 (IC₅₀, 322 nM) ^[1]. INCB018424 inhibits IL-6 signaling (IC₅₀, 281 nM), and proliferation of JAK2V617F⁺ Ba/F3 cells (IC₅₀, 126 nM) as well as HEL cells (IC₅₀, 186 nM) with JAK2 mutation. INCB018424 preferentially suppresses erythroid progenitor colony formation from JAK2V617F⁺ PV patients (IC₅₀, 67 nM) versus healthy donors (IC₅₀, >400 nM). In a mouse model of JAK2V617F⁺ MPN, oral INCB018424 markedly reduces splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminates neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. The preclinical results support its clinical evaluation as a promising oral agent for the treatment of myeloproliferative neoplasms (MPNs), including MF, PV, and ET ^[2-3]. INCB018424 appears safe and well-tolerated dose of 15 mg BID and demonstrates preliminary efficacy in the treatment of Rheumatoid arthritis (RA) ^[4].

Chemical Properties