Kinetically selective and potent inhibitors of HDAC8.

HDAC8 is an established and validated target for T-cell lymphoma and childhood neuroblastoma. The active site binding pocket of HDAC8 is highly conserved among all zinccontaining representatives of the histone deacetylase family. This explains that most HDACs are unselectively recognized by similar inhibitors featuring a zinc binding group (ZBG), a hydrophobic linker and a head group. In the light of this difficulty, the creation of isoenzymeselectivity is one of the major challenges in the development of HDAC inhibitors. In a series of trifluoromethylketone inhibitors of HDAC8 compound 10 shows a distinct binding mechnism and a dramatically increased residence time providing kinetic selectivity against HDAC4. Combining the binding kinetics results with computational docking and binding site flexibility analysis suggests that 10 occupies the conserved catalytic site as well as an adjacent transient sub-pocket of HDAC8.