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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2182-2189
Number of pages8
JournalACS Medicinal Chemistry Letters
Volume11
Issue number11
DOIs
StatePublished - Nov 12 2020
Externally publishedYes

Keywords

  • HO
  • JAK3 covalent inhibitor
  • Prodrug
  • rheumatoid arthritis

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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