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

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

Affiliation

  • 1 Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. joey_methot@merck.com
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.

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