脱甲基酶
化学
酶
生物化学
苯并咪唑
作用机理
亚科
结合位点
体外
表观遗传学
基因
有机化学
作者
David M. Carter,Edgar Specker,P. Malecki,Jessica Przygodda,Krystyna Dudaniec,M.S. Weiss,Udo Heinemann,Marc Nazaré,U. Gohlke
标识
DOI:10.1021/acs.jmedchem.1c00693
摘要
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 Fe2+ 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI