Hydrogen Peroxide Inducible JAK3 Covalent Inhibitor: Prodrug for the Treatment of RA with Enhanced Safety Profile

Qichao Bao; Liangying Zhang; Nan Wang; Brian Gabet; Weikang Yang; Xingyang Gao; Qidong You; Zhengyu Jiang

doi:10.1021/acsmedchemlett.0c00323

Hydrogen Peroxide Inducible JAK3 Covalent Inhibitor: Prodrug for the Treatment of RA with Enhanced Safety Profile

ACS Med Chem Lett. 2020 Oct 5;11(11):2182-2189. doi: 10.1021/acsmedchemlett.0c00323. eCollection 2020 Nov 12.

Authors

Qichao Bao^{1

2}, Liangying Zhang^{1

2}, Nan Wang³, Brian Gabet³, Weikang Yang^{1

2}, Xingyang Gao^{1

2}, Qidong You^{1

2}, Zhengyu Jiang^{1

2}

Affiliations

¹ State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
² Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
³ Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street, SE, Minneapolis, Minnesota 55414, United States.

Abstract

Selective inhibition of Janus kinases (JAKs) is an arising strategy in drug discovery. Covalent inhibitors targeting a unique cysteine in JAK3 exhibit ultraselectivity among JAK family members. However, safety and tissue specific concerns still remain. A prodrug of a known JAK3 covalent inhibitor sensitive to H₂O₂ was designed and synthesized and its therapeutic effect was evaluated in the CIA (collagen-induced arthritis) mice model of RA (rheumatoid arthritis). The prodrug strategy relied on the introduction of a hydrogen peroxide-sensitive borate trigger group to avoid random covalent binding to thiol functionalities in biomacromolecules. The results show that the prodrug can be activated and released under pathophysiological concentration of H₂O₂. In addition, the prodrug demonstrated stability to the physiological environment. In comparison to the parent compound, the prodrug showed a similar therapeutic effect in the CIA model but notably exhibited lower toxicity and a larger therapeutic window.