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

European Journal of Medicinal Chemistry
Bing ZhaoHong-Min Liu

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.

Citations

Apr 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nagaraju KerruSreekantha B Jonnalagadda
Jan 21, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nikita P Burlutskiy, Andrei S Potapov
Feb 19, 2021·Journal of Hematology & Oncology·Guan-Jun YangJiong Chen

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.