6G5X

Crystal Structure of KDM4A with compound YP-02-145

Summary for 6G5X

• Entry DOI: 10.2210/pdb6g5x/pdb
• Descriptor: Lysine-specific demethylase 4A, ZINC ION, NICKEL (II) ION, ... (8 entities in total)
• Functional Keywords: kdm4a, ligand binding, drug design, inhibitor design, cancer, epigenetics, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 85151.74

Authors

Malecki, P.H.,Carter, D.M.,Gohlke, U.,Specker, E.,Nazare, M.,Weiss, M.S.,Heinemann, U. (deposition date: 2018-03-30, release date: 2019-04-10, Last modification date: 2024-01-31)

Primary citation

Carter, D.M.,Specker, E.,Malecki, P.H.,Przygodda, J.,Dudaniec, K.,Weiss, M.S.,Heinemann, U.,Nazare, M.,Gohlke, U.
Enhanced Properties of a Benzimidazole Benzylpyrazole Lysine Demethylase Inhibitor: Mechanism-of-Action, Binding Site Analysis, and Activity in Cellular Models of Prostate Cancer.
J.Med.Chem., 64:14266-14282, 2021

PubMed 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 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.

PubMed: 34555281
DOI: 10.1021/acs.jmedchem.1c00693

Experimental method

X-RAY DIFFRACTION (1.78 Å)