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

  • Bioorg Med Chem Lett. 2008 Feb 1;18(3):973-8. doi: 10.1016/j.bmcl.2007.12.031.
Joey L Methot  1 ,  Prasun K Chakravarty ,  Melissa Chenard ,  Joshua Close ,  Jonathan C Cruz ,  William K Dahlberg ,  Judith Fleming ,  Christopher L Hamblett ,  Julie E Hamill ,  Paul Harrington ,  Andreas Harsch ,  Richard Heidebrecht ,  Bethany Hughes ,  Joon Jung ,  Candia M Kenific ,  Astrid M Kral ,  Peter T Meinke ,  Richard E Middleton ,  Nicole Ozerova ,  David L Sloman ,  Matthew G Stanton ,  Alexander A Szewczak ,  Sriram Tyagarajan ,  David J Witter ,  J Paul Secrist ,  Thomas A Miller
Affiliations
  • 1. Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. [email protected]
PMID: 18182289 DOI: 10.1016/j.bmcl.2007.12.031
Abstract

We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 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-1:2 extend the existing HDAC Inhibitor pharmacophore to include an internal binding domain.