Discovery of Novel Pyrazole-Based KDM5B Inhibitor TK- 129 and Its Protective Effects on Myocardial Remodeling and Fibrosis

  • J Med Chem. 2022 Oct 13;65(19):12979-13000. doi: 10.1021/acs.jmedchem.2c00797.
Kai Tang  1 ,  Le-Min Jiao  1 ,  Yu-Ruo Qi  1 ,  Tian-Ci Wang  1 ,  Ya-Lan Li  1 ,  Jia-Le Xu  1 ,  Zi-Wei Wang  1 ,  Bin Yu  1 ,  Hong-Min Liu  1 ,  Wen Zhao  1
Affiliations
  • 1. State Key Laboratory of Esophageal Cancer Prevention and Treatment; Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China.
PMID: 36112701 DOI: 10.1021/acs.jmedchem.2c00797
Abstract

Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK-129 (IC50 = 0.044 μM). TK-129 reduced Ang II-induced activation of cardiac fibroblasts in vitro, exhibited good PK profile (F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK-129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK-129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis.

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