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
  • 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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