RESUMEN
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.
Asunto(s)
Histona Demetilasas , Histonas , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Histonas/metabolismo , Histona Demetilasas con Dominio de Jumonji/química , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Catálisis , CromatinaRESUMEN
We previously identified two structurally related pyrazolone (compound 1) and pyridazine (compound 2) allosteric inhibitors of DNMT3A through screening of a small chemical library. Here, we show that these compounds bind and disrupt protein-protein interactions (PPIs) at the DNMT3A tetramer interface. This disruption is observed with distinct partner proteins and occurs even when the complexes are acting on DNA, which better reflects the cellular context. Compound 2 induces differentiation of distinct myeloid leukemia cell lines including cells with mutated DNMT3A R882. To date, small molecules targeting DNMT3A are limited to competitive inhibitors of AdoMet or DNA and display extreme toxicity. Our work is the first to identify small molecules with a mechanism of inhibition involving the disruption of PPIs with DNMT3A. Ongoing optimization of compounds 1 and 2 provides a promising basis to induce myeloid differentiation and treatment of diseases that display aberrant PPIs with DNMT3A, such as acute myeloid leukemia.