A novel class of anthraquinone-based HDAC6 inhibitors.

Histone deacetylase 6 (HDAC6) is an important target for the treatment of diverse diseases including cancer, neurodegenerative diseases, autoimmune disorders, inflammation, drug addiction, and viral infection. Therefore, the discovery of HDAC6-isoform selective inhibitors is of high importance for clinical applications. Here, we present an approach to discover HDAC6-isoform selective inhibitors. To our best knowledge, we for the first time perform a virtual screening campaign in the surface and channel region of HDAC6 enzyme, followed by rational installation of zinc binding group for the development of HDAC6-isoform selective inhibitors. Consequently, this approach establishes the proof of principle for the discovery of HDAC6-isoform selective inhibitors and successfully provides our lead compound 3. In particular, compound 3 inhibits HDAC6 enzyme with an IC50 value of 56 nM and displays an excellent HDAC6 selectivity over other HDAC isoforms in HDAC enzyme assay. Furthermore, the exposure of SH-SY5Y cells with compound 3 significantly promotes the acetylation of α-tubulin at the low concentration of 0.5 µM, but not the acetylation of Histone H3 up to 20 µM. Thus, our lead compound 3 represents a novel HDAC6-isoform selective inhibitor and warrants further studies for therapeutic evaluation.

Aspirin-inspired acetyl-donating HDACs inhibitors.

Aspirin is one of the oldest drugs for the treatment of inflammation, fever, and pain. It is reported to covalently modify COX-2 enzyme by acetylating a serine amino acid residue. By virtue of aspirin's acetylating potential, we for the first time developed novel acetyl-donating HDAC inhibitors. In this study, we report the design, synthesis, in silico docking study, and biological evaluation of acetyl-donating HDAC inhibitors. The exposure of MDA-MB-231 cells with compound 4c significantly promotes the acetylation of α-tubulin and histone H3, which are substrates of HDAC6 and HDAC1, respectively. In silico docking simulation also indicates that compound 4c tightly binds to the deep substrate-binding pocket of HDAC6 by coordinating the active zinc ion in a bidentate manner and forming hydrogen bond interactions with Ser531 and His573 amino acid residues. In particular, compound 4c (GI50 = 147 µM) affords the significant enhancement of anti-proliferative effect on MDA-MB-231 cells, compared with its parent compound 2c (GI50 > 1000 µM) and acetyl-donating group deficient compound 6 (GI50 = 554 µM). Overall, compound 4c presents a novel strategy for developing acetyl-donating HDAC inhibitors.