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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., Specker, E., Malecki, P.H., Przygodda, J., Dudaniec, K., Weiss, M.S., Heinemann, U., 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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