Small molecule inhibitors of histone acetyltransferase Tip60

Tip60 is a key member of the MYST family of histone acetyltransferases and involved in a broad spectrum of cellular pathways and disease conditions. So far, small molecule inhibitors of Tip60 and other members of MYST HATs are rarely reported. To discover new small molecule inhibitors of Tip60 as mechanistic tools for functional study and as chemical leads for therapeutic development, we performed virtual screening using the crystal structure of Esa1 (the yeast homolog of Tip60) on a small molecule library database. Radioactive acetylation assays were carried out to further evaluate the virtual screen hits. Several compounds with new structural scaffolds were identified with micromolar inhibition potency for Tip60 from the biochemical studies. Further, computer modeling and kinetic assays suggest that these molecules target the acetyl-CoA binding site in Tip60. These new inhibitors provide valuable chemical hits to develop further potent inhibitors for the MYST HATs.

Graphical abstractSeveral small molecules were identified as micromolar inhibitors of histone acetyltransferase Tip60. Docking and kinetic analyses suggest that they bind to the active site of the enzyme.Figure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights► A set of small molecules are discovered as inhibitors of HAT Tip60. ► Docking study shows that these molecules target acetyl-CoA binding site. ► Kinetic analysis confirms that the inhibitors compete with the cofactor.