Discovery of Highly Selective HDAC2 Inhibitors in Cells That Elevate Histone Acetylation In Vivo without Adverse Effects from Dual Inhibition of HDAC1 and 2

Alzheimer’s disease impairs the cognitive domain
of learning
and memory through synaptic dysfunction. Memory formation requires
gene expression to facilitate synaptic plasticity. When HDAC2 is inhibited,
elevated histone acetylation promotes the gene expressions critical
for synaptic plasticity and thus facilitates memory formation. However,
simultaneous inhibition of HDAC1 and HDAC2 leads to hematologic toxicity.
As the two isoforms have high homology, it is a challenge to identify
selective HDAC2 inhibitors. Here, we report the development of novel
cellular assays to determine HDAC2 potency and selectivity over HDAC1.
Our HTS campaign using cellular assays for both isoforms identified 6 as a selective hit compound. With optimization efforts focusing
on balancing cellular potency, selectivity, and mitigating BCRP recognition,
we discovered compound 11, which exhibited significant
in vivo efficacy in elevating histone acetylation levels and enhancing
LTP. Importantly, 11 showed no significant hematological
toxicity in human blood cells derived from simultaneous inhibition
of HDAC1 and HDAC2.