Structural Aspects of Small-Molecule Inhibition of Methyllysine Reader Proteins

Abstract

Methyl reader proteins recognize and bind to post-translationally methylated residues. They execute the commands issued by protein methyltransferases and play functional roles in diverse cellular processes including gene regulation, development and oncogenesis. Efforts to inhibit these proteins are relatively new. Only a small number of methyl reader proteins belonging to the chromodomain, malignant brain tumor domain, plant homeodomain finger and Tudor domain families have been targeted by chemical inhibitors. This review summarizes inhibitors that have been reported to date, and provides a perspective for future progress. Structural determinants for methyl reader inhibition will be presented, along with an analysis of the molecular interactions that control potency and selectivity for inhibitors of each family.

Chemical modulators for epigenome reader domains as emerging epigenetic therapies for cancer and inflammation

“…[5] Methyl-lysine reader domains are emerging as an important class of targets with antagonists reported for members of the former four families. The latter four families along with another family, the plant Agenet domains, collectively embody the Royal family domains.…”

“…Such tightly regulated molecular activities provide opportunities for therapeutic intervention of PPIs with small molecule chemical inhibitors designed to target acetyl-lysine binding bromodomains (BrDis) or methyl-lysine binding chromodomains (ChDis). [4, 5] Common PTMs include histone lysine acetylation (KAc) and histone lysine mono-, di- or tri-methylation (Kme, Kme2, or Kme3). For the purposes of transcription, acetylation PTM is implicated in activation, while methylation PTMs are associated with either gene activation or silencing.…”

Pan-Specific and Partially Selective Dye-Labeled Peptidic Inhibitors of the Polycomb Paralog Proteins

“…The challenges associated with screening small molecules against the CBX proteins have also been reported by others. 9,11,12 We have previously reported a peptide-driven approach to identify a series of submicromolar inhibitors targeting CBX4/CBX7 and CBX6. [12][13][14] Potent peptidic inhibitors of CBX4/CBX7 have also been identified by the Frye group and have shown activity in cellular based studies.…”

Recognition of stapled histone H3K4me3 peptides by epigenetic reader proteins

“…Taken together, the results demonstrate that the same stapled H3K4me3 peptides display binding selectivity for BPTF PHD and JMJD2A TTD over JARID1A PHD3 , knowledge that can be used in the rational design of probes targeting reader domain proteins. 35–37…”

“…Taken together, the results demonstrate that the same stapled H3K4me3 peptides display binding selectivity for BPTF PHD and JMJD2A TTD over JARID1A PHD3 , knowledge that can be used in the rational design of probes targeting reader domain proteins. [35][36][37] The potential binding modes of tightest binding peptides 3 (BPTF PHD ) and 4 (JMJD2A TTD ) were subsequently investigated with computational methods. Induced-fit dockings were performed using the X-ray structures of BPTF PHD and JMJD2A TTD in complex with H3K4me3 peptides.…”