ml6b00124_si_001.pdf (23.47 MB)
Structural Requirements of HDAC Inhibitors: SAHA Analogues Modified at the C2 Position Display HDAC6/8 Selectivity
journal contribution
posted on 2017-02-07, 00:00 authored by Ahmed
T. Negmeldin, Geetha Padige, Anton V. Bieliauskas, Mary Kay H. PflumHistone deacetylase
(HDAC) proteins are epigenetic regulators that
deacetylate protein substrates, leading to subsequent changes in cell
function. HDAC proteins are implicated in cancers, and several HDAC
inhibitors have been approved by the FDA as anticancer drugs, including
SAHA (suberoylanilide hydroxamic acid; Vorinostat and Zolinza). Unfortunately,
SAHA inhibits most HDAC isoforms, which limits its use as a pharmacological
tool and may lead to side effects in the clinic. In this work SAHA
analogues substituted at the C2 position were synthesized and screened
for HDAC isoform selectivity in vitro and in cells.
The most potent and selective compound, C2-n-hexyl
SAHA, displayed submicromolar potency with 49- to 300-fold selectivity
for HDAC6 and HDAC8 compared to HDAC1, -2, and -3. Docking studies
provided a structural rationale for selectivity. Modification of the
nonselective inhibitor SAHA generated HDAC6/HDAC8 dual selective inhibitors,
which can be useful lead compounds toward developing pharmacological
tools and more effective anticancer drugs.