2. Academic Validation
  3. A JAK tyrosine kinase and pseudokinase Co-inhibition strategy combines enhanced potency and on-demand activation

A JAK tyrosine kinase and pseudokinase Co-inhibition strategy combines enhanced potency and on-demand activation

  • Eur J Med Chem. 2023 Mar 15;250:115198. doi: 10.1016/j.ejmech.2023.115198.
Xuetao Chen 1,  Liangying Zhang 2,  Qichao Bao 3,  Fanying Meng 1,  Chihong Liu 1,  Rujun Xu 1,  Xinrui Ji 1,  Qidong You 4,  Zhengyu Jiang 5
Affiliations

Affiliations

  • 1 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Pharmacy, Hunan Food and Drug Vocational College, Changsha, 410208, China.
  • 3 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
  • 4 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 5 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
PMID: 36805946 DOI: 10.1016/j.ejmech.2023.115198
Abstract

Janus tyrosine kinase (JAK) inhibitors have been on the market for several years, but their use is limited by drug resistance and intolerable side effects. Herein, we propose a novel strategy of JAK tyrosine kinase (TK) and pseudokinase (PK) domain co-inhibition system to consolidate robust JAK inhibition and on-demand activation. A photoexcited prodrug PAT-SIL-TG-1&AT exhibits the synergy effects of TK-PK co-inhibition and enable the spatiotemporal control of JAK2 signaling. The hypoxia-activated prodrug HAT-SIL-TG-1&AT significantly inhibited HEL cells proliferation and downregulated phosphorylated STAT3/5 under hypoxic conditions. Importantly, HAT-SIL-TG-1&AT showed synergistic antitumor effects and selectively inhibited the JAK-STAT signaling in tumor tissues in vivo. This work demonstrates a viable solution to achieve superior JAK2 inhibition, and provides an inspiration for other kinases containing PK domain.

Keywords

Co-inhibition; JAK; Produrg; Pseudokinase; Tyrosine kinase.

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