Design of anticancer drugs based on a chromatin-remodeling mechanism

The control of the enzymatic machinery implicated in the (un)packing of chromatin, such as the reversible acetylation (HAT enzymes)/deacetylation (HDAC enzymes) of lysine residues, the methylation/demethylation of histone lysine and arginine residues, and the DNA methylation (DNMT enzymes)/demethylation, is an important step in the regulation of transcriptional events. As a consequence, chromatin- remodeling enzymes, in particular HDACsand DNMTs, have recently emerged as new promising targets of the socalled “epigenetic drugs” for the treatment of cancer. A series of structurally diverse compounds endowed with cytotoxic properties, has been identified by a three-dimensional pharmacophore model, validated utilizing known HDAC inhibitors, and database searching. A search of a small-molecule databases of ~350,000 compounds, allowed the identification of 60 compounds. We tested these compounds in four human cancer cell lines from different tumor origins. Among them, compound 3 showed good activity in all tested cell lines and compound 4 exhibited a selective activity in MDA-MB435 cell line, with IC50 values in the low micromolar range. These compounds warrant further development and optimization.