Discovery of a potent, selective, and covalent ZAP-70 kinase inhibitor

Danni Rao; Heng Li; Xuelian Ren; Yaoliang Sun; Cuiyun Wen; Mingyue Zheng; He Huang; Wei Tang; Shilin Xu

doi:10.1016/j.ejmech.2021.113393

Discovery of a potent, selective, and covalent ZAP-70 kinase inhibitor

Eur J Med Chem. 2021 Jul 5:219:113393. doi: 10.1016/j.ejmech.2021.113393. Epub 2021 Mar 30.

Authors

Danni Rao¹, Heng Li², Xuelian Ren³, Yaoliang Sun⁴, Cuiyun Wen⁴, Mingyue Zheng⁵, He Huang⁶, Wei Tang⁷, Shilin Xu⁸

Affiliations

¹ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, #555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Science, 19 Yuquan Road, Beijing, 110039, China.
² Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
³ Center for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁴ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, #555 Zu Chong Zhi Road, Shanghai, 201203, China.
⁵ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Science, 19 Yuquan Road, Beijing, 110039, China.
⁶ Center for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Science, 19 Yuquan Road, Beijing, 110039, China.
⁷ Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Science, 19 Yuquan Road, Beijing, 110039, China. Electronic address: tangwei@simm.ac.cn.
⁸ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, #555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Science, 19 Yuquan Road, Beijing, 110039, China. Electronic address: slxu@simm.ac.cn.

PMID: 33845236
DOI: 10.1016/j.ejmech.2021.113393

Abstract

ZAP-70 (zeta-chain associated protein kinase 70 kDa) signaling pathway and its functions have been involved in the development and adaptive immune signaling of T cell. It thus represents a promising target for autoimmune diseases. Although reversible ZAP-70 kinase domain inhibitors have been developed, they are either weak or nonselective. We report herein the structure-guided development of the first potent and covalent inhibitor of ZAP-70 kinase domain. In particular, compound 18 (RDN009) showed good selectivity for ZAP-70 over structurally related Syk, and displayed potent inhibitory effects on T cell proliferation, activation, and inflammatory cytokine production. A mass spectrometry analysis further confirmed the covalent linkage between the inhibitor and ZAP-70 protein at C346. Overall, the covalent inhibitor RDN009 represents a potent and selective probe of ZAP-70 for further development for treatment of autoimmune diseases.

Keywords: Autoimmune diseases; Covalent inhibitor; T cell; Zeta-chain associated protein kinase 70 kDa (ZAP-70).

MeSH terms

Animals
Binding Sites
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / metabolism
Cell Proliferation / drug effects
Cytokines / analysis
Cytokines / metabolism
Drug Evaluation, Preclinical
Humans
Mice
Mice, Inbred BALB C
Molecular Docking Simulation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Structure-Activity Relationship
Syk Kinase / antagonists & inhibitors
Syk Kinase / metabolism
ZAP-70 Protein-Tyrosine Kinase / antagonists & inhibitors*
ZAP-70 Protein-Tyrosine Kinase / metabolism

Substances

Cytokines
Protein Kinase Inhibitors
Syk Kinase
ZAP-70 Protein-Tyrosine Kinase
ZAP70 protein, human