Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors

Herein we report the discovery of a family of novel yet simple, amino-acid derived class I HDAC inhibitors that demonstrate isoform selectivity via access to the internal acetate release channel. Isoform selectivity criteria is discussed on the basis of X-ray crystallography and molecular modeling of these novel inhibitors bound to HDAC8, potentially revealing insights into the mechanism of enzymatic function through novel structural features revealed at the atomic level.

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► Amino-acid derived HDAC8 small molecule inhibitors.
► α-Amino-ketone Zn binding allows synthetic access to the acetate release channel.
► HDAC8 selectivity achieved over isoforms HDAC1, 2 and 6.
► Hypothesis of acetate release presented from catalytic lysine deacetylation.