Recent developments in catalysis and inhibition of the Jumonji histone demethylases

Abstract

Histone methylation, one of the most common histone modifications, has fundamental roles in regulating chromatin-based processes. Jumonji histone lysine demethylases (JMJC KDMs) influence regulation of gene transcription through both their demethylation and chromatin scaffolding functions. It has recently been demonstrated that dysregulation of JMJC KDMs contributes to pathogenesis and progression of several diseases, including cancer. These observations have led to an increased interest in modulation of enzymes that regulate lysine methylation. Here, we highlight recent progress in understanding catalysis of JMJC KDMs. Specifically, we focus on recent research advances on elucidation of JMJC KDM substrate recognition and interactomes. We also highlight recently reported JMJC KDM inhibitors and describe their therapeutic potentials and challenges. Finally, we discuss alternative strategies to target these enzymes, which rely on targeting JMJC KDMs accessory domains as well as utilization of the targeted protein degradation strategy.

Keywords: Allosteric inhibitors; Catalysis; Domain crosstalk; Jumonji histone demethylases; Lysine demethylation; Orthosteric inhibitors; Post-translational modifications.