Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis.

Abstract

Selective inhibition of Janus kinase 3 (JAK3) has been identified as an important strategy for the treatment of autoimmune disorders. Based on the unique cysteine 909 residue (Cys909) of JAK3 at the gatekeeper position, we have developed a new irreversible covalent inhibitor, III-4, which is highly potent and selective in targeting JAK3. Importantly, III-4 selectively inhibited JAK3 (IC50 = 57 ± 1.21 nM) over other JAKs (IC50 > 10 µM) and Cys909 kinome members (IC50 > 1 µM). A cellular selectivity study also confirmed that III-4 preferentially inhibited JAK3 over JAK1 in JAK/STAT signaling. Moreover, the fact that III-4 covalently modified the Cys909 residue in JAK3 was clearly validated by mass spectrometry and covalent docking analysis. Based on the favorable target profiles, the pharmacokinetic properties and its low toxicity, III-4 exhibited better efficacy than tofacitinib in impeding disease progression in CIA mice, without any significant adverse effects. Taken together, III-4 is a potent, selective, and durable inhibitor of JAK3 and has the potential for the treatment of inflammatory disorders and autoimmune diseases, such as rheumatoid arthritis.