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Enhanced properties of a benzimidazole benzylpyrazole lysine demethylase inhibitor: mechanism-of-action, binding site analysis, and activity in cellular models of prostate cancer

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Item Type:Article
Title:Enhanced properties of a benzimidazole benzylpyrazole lysine demethylase inhibitor: mechanism-of-action, binding site analysis, and activity in cellular models of prostate cancer
Creators Name:Carter, D.M. and Specker, E. and Malecki, P.H. and Przygodda, J. and Dudaniec, K. and Weiss, M.S. and Heinemann, U. and Nazaré, M. and Gohlke, U.
Abstract:Jumonji domain-containing lysine demethylase (KDM) enzymes are encoded by genes of the KDM superfamily. Activities of the KDM4 subfamily promote aggressive phenotypes associated with prostate cancer (PCa). Previously, we discovered a benzimidazole pyrazole molecule that inhibited KDM4 isoforms with properties tractable for development. Here, we demonstrate that a benzyl-substituted variant of this inhibitor exhibits improved potency in biochemical assays, is cell-permeable, and kills PCa cells at low micromolar concentrations. By X-ray crystallography and kinetics-based assays, we demonstrate that the mechanism of inhibition is complex, proceeding via competition with the enzyme for binding of active-site Fe(2+) and by populating a distal site on the enzyme surface. Furthermore, we provide evidence that the inhibitor's cytostatic properties arise from direct intracellular inhibition of KDM4 enzymes. PCa cells treated with the inhibitor exhibit reduced expression of genes regulated by the androgen receptor, an outcome accompanied by epigenetic maintenance of a heterochromatic state.
Keywords:Antitumor Drug Screening Assays, Benzimidazoles, Binding Sites, Cell Survival, Cultured Tumor Cells, Drug Dose-Response Relationship, Enzyme Inhibitors, Jumonji Domain-Containing Histone Demethylases, Molecular Models, Molecular Structure, Pyrazoles, Structure-Activity Relationship, X-Ray Crystallography
Source:Journal of Medicinal Chemistry
ISSN:0022-2623
Publisher:American Chemical Society
Volume:64
Number:19
Page Range:14266-14282
Date:14 October 2021
Official Publication:https://doi.org/10.1021/acs.jmedchem.1c00693
PubMed:View item in PubMed

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