Identification of novel small-molecule ligands of methyl-lysine binding protein PHF20

Methylation of histone tails influences overall chromatin structure and the accessibility of DNA segments, thus representing a crucial post-translational modification involved in gene regulation. Recognition of these methyl marks has been attributed to the “Royal Family” of proteins, which includes the Tudor domain subfamily. The ability of these enzymes in binding lysine-methylated protein substrate has been well documented. However, much remains to be elucidated with regard to precise mechanisms by which such interactions influence the processes of transcription, translation and RNA splicing. Among the “readers”, the Plant Homeodomain Finger protein 20 (PHF20, Figure1) is a transcription factor, which was originally identified in glioma patients. While little is known about its cognate cellular role, PHF20 is prevalent in hepatocellular tumors of stage I and is also abundantly expressed in both advanced small-cell lung cancer and advanced adenocarcinoma, indicating that PHF20 might be tumor-associated antigen and could play a role in cancer progression. Prompted by our interest in the discovery of small molecule modulators of epigenetic targets, here we report the identification of a series of inhibitors of PHF20, that might represent new opportunities to investigate the role of this protein in chromatin biology and drug discovery.