1 research outputs found
Divergent Kinetics Differentiate the Mechanism of Action of Two HDAC Inhibitors
Histone
deacetylases (HDACs) play diverse roles in many diseases including
cancer, sarcopenia, and Alzheimer’s. Different isoforms of
HDACs appear to play disparate roles in the cell and are associated
with specific diseases; as such, a substantial effort has been made
to develop isoform-selective HDAC inhibitors. Our group focused on
developing HDAC1/HDAC2-specific inhibitors as a cancer therapeutic.
In the course of characterizing the mechanism of inhibition of a novel
HDAC1/2-selective inhibitor, it was determined that it did not exhibit
classical Michaelis–Menten kinetic behavior; this result is
in contrast to the seminal HDAC inhibitor SAHA. Enzymatic assays,
along with a newly developed binding assay, were used to determine
the rates of binding and the affinities of both the HDAC1/2-selective
inhibitor and SAHA. The mechanism of action studies identified a potential
conformational change required for optimal binding by the selective
inhibitor. A model of this putative conformational change is proposed