Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

Identification of a novel benzimidazole pyrazolone scaffold that inhibits KDM4 lysine demethylases and reduces proliferation of prostate cancer cells

[img]
Preview
PDF (Accepted manuscript (final draft)) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
3MB

Item Type:Article
Title:Identification of a novel benzimidazole pyrazolone scaffold that inhibits KDM4 lysine demethylases and reduces proliferation of prostate cancer cells
Creators Name:Carter, D.M. and Specker, E. and Przygodda, J. and Neuenschwander, M. and von Kries, J.P. and Heinemann, U. and Nazaré, M. and Gohlke, U.
Abstract:Human lysine demethylase (KDM) enzymes (KDM1-7) constitute an emerging class of therapeutic targets, with activities that support growth and development of metastatic disease. By interacting with and co-activating the androgen receptor, the KDM4 subfamily (KDM4A-E) promotes aggressive phenotypes of prostate cancer (PCa). Knockdown of KDM4 expression or inhibition of KDM4 enzyme activity reduces the proliferation of PCa cell lines and highlights inhibition of lysine demethylation as a possible therapeutic method for PCa treatment. To address this possibility, we screened the ChemBioNet small molecule library for inhibitors of the human KDM4E isoform and identified several compounds with IC50 values in the low micromolar range. Two hits, validated as active by an orthogonal enzyme-linked immunosorbent assay, displayed moderate selectivity toward the KDM4 subfamily and exhibited antiproliferative effects in cellular models of PCa. These compounds were further characterized by their ability to maintain the transcriptionally silent histone H3 tri-methyl K9 epigenetic mark at subcytotoxic concentrations. Taken together, these efforts identify and validate a hydroxyquinoline scaffold and a novel benzimidazole pyrazolone scaffold as tractable for entry into hit-to-lead chemical optimization campaigns.
Keywords:Epigenetics, Iysine Demethylase (KOM), Cancer, High-Throughput Screening (HTS)
Source:SLAS Discovery
ISSN:2472-5552
Publisher:Sage Publications (U.S.A.)
Volume:22
Number:7
Page Range:801-812
Date:1 August 2017
Additional Information:Copyright © 2017 Society for Laboratory Automation and Screening
Official Publication:https://doi.org/10.1177/2472555217699157
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library