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

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.

• Authors: Bing Zhao, Qianqian Liang, Hongmei Ren, Xinhui Zhang, Yang Wu, Kun Zhang, Li-Ying Ma, Yi-Chao Zheng, Hong-Min Liu
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 192 Pg. 112161 (Apr 15 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 32155529 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Nuclear Proteins
• Pyrazoles
• Repressor Proteins
• pyrazole
• Jumonji Domain-Containing Histone Demethylases
• KDM5B protein, human

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Jumonji Domain-Containing Histone Demethylases
• Molecular Structure
• Nuclear Proteins
• Pyrazoles (chemical synthesis, chemistry, pharmacology)
• Repressor Proteins
• Structure-Activity Relationship
• Tumor Cells, Cultured
• Wound Healing (drug effects)