Design and synthesis of highly selective Janus kinase 3 covalent inhibitors for the treatment of rheumatoid arthritis

• Published in: Archiv der Pharmazie (Weinheim) 2024-06, Vol.357 (6), p.e2300753-n/a
• Main Authors: Yao, Hualiang, Zhang, Jie, Zheng, Qisheng, Zeng, Xianxia, Huang, Huaizheng, Ling, Zhen, Tang, Minghai, Chen, Zhiquan, Wang, Wenchu, He, Linhong
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Experimental - chemically induced; Arthritis, Experimental - drug therapy; Arthritis, Experimental - enzymology; Arthritis, Rheumatoid - drug therapy; covalent inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; JAK3; Janus Kinase 3 - antagonists & inhibitors; Janus Kinase 3 - metabolism; Male; Mice; Mice, Inbred DBA; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; rheumatoid arthritis; selectivity; Structure-Activity Relationship
• ISSN: 0365-6233; 1521-4184; 1521-4184
• DOI: 10.1002/ardp.202300753

Selective inhibition of Janus kinase 3 (JAK3) is a promising strategy for the treatment of autoimmune diseases. Based on the discovery of a hydrophobic pocket unutilized between the lead compound RB1 and the JAK3 protein, a series of covalent JAK3 inhibitors were prepared by introducing various aromatic fragments to RB1. Among them, J1b (JAK3 IC50 = 7.2 nM, other JAKs IC50 > 1000 nM) stood out because of its low toxicity (MTD > 2 g/kg) and superior anti‐inflammatory activity in Institute of Cancer Research mice. Moreover, the acceptable bioavailability (F% = 31.69%) ensured that J1b displayed excellent immune regulation in collagen‐induced arthritis mice, whose joints in the high‐dose group were almost recovered to a normal state. Given its clear kinase selectivity (Bmx IC50 = 539.9 nM, other Cys909 kinases IC50 > 1000 nM), J1b was nominated as a highly selective JAK3 covalent inhibitor, which could be used to safely treat arthritis and other autoimmune diseases. A more potent JAK3 inhibitor, J1b, was synthesized by introducing a 3‐nitrophenyl on RB1 to increase hydrophobic interactions. J1b maintained low toxicity in vivo and displayed an excellent antiarthritic effect in collagen‐induced arthritis mice, demonstrating that J1b is an experimental and potential candidate for the treatment of rheumatoid arthritis.