Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2).

ABSTRACT

We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-12). Optimized SHI-12 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-12 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.