2. Academic Validation
  3. Discovery of pyrazole derivatives as cellular active inhibitors of histone lysine specific demethylase 5B (KDM5B/JARID1B)

Discovery of pyrazole derivatives as cellular active inhibitors of histone lysine specific demethylase 5B (KDM5B/JARID1B)

  • Eur J Med Chem. 2020 Apr 15;192:112161. doi: 10.1016/j.ejmech.2020.112161.
Bing Zhao 1,  Qianqian Liang 1,  Hongmei Ren 1,  Xinhui Zhang 1,  Yang Wu 1,  Kun Zhang 1,  Li-Ying Ma 2,  Yi-Chao Zheng 3,  Hong-Min Liu 4
Affiliations

Affiliations

  • 1 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Pharmaceutical research and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China.
  • 2 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Pharmaceutical research and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: [email protected].
  • 3 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Pharmaceutical research and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: [email protected].
  • 4 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Pharmaceutical research and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: [email protected].
PMID: 32155529 DOI: 10.1016/j.ejmech.2020.112161
Abstract

KDM5B (also known as PLU-1 and JARID1B) is 2-oxoglutarate and Fe2+ dependent oxygenase that acts as a histone H3K4 demethylase, which is a key participant in inhibiting the expression of tumor suppressors as a drug target. Here, we present the discovery of pyrazole derivatives compound 5 by structure-based virtual screening and biochemical screening with IC50 of 9.320 μM against KDM5B, and its subsequent optimization to give 1-(4-methoxyphenyl)-N-(2-methyl-2-morpholinopropyl)-3-phenyl-1H-pyrazole-4-carboxamide (27 ab), a potent KDM5B inhibitor with IC50 of 0.0244 μM. In MKN45 cells, compound 27 ab can bind and stabilize KDM5B and induce the accumulation of H3K4me2/3, bona fide substrates of KDM5B, while keep the amount of H3K4me1, H3K9me2/3 and H3K27me2 without change. Further biological study also indicated that compound 27 ab is a potent cellular active KDM5B inhibitor that can inhibit MKN45 cell proliferation, wound healing and migration. In sum, our finding gives a novel structure for the discovery of KDM5B inhibitor and targeting KDM5B may be a new therapeutic strategy for gastric Cancer treatment.

Keywords

Gastric cancer; Inhibitor; KDM5B; Pyrazole derivative.

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