Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors

  • Bioorg Med Chem. 2011 Aug 1;19(15):4626-34. doi: 10.1016/j.bmc.2011.06.030.
Lewis Whitehead  1 ,  Markus R Dobler ,  Branko Radetich ,  Yanyi Zhu ,  Peter W Atadja ,  Tavina Claiborne ,  Jonathan E Grob ,  Andrew McRiner ,  Margaret R Pancost ,  Anup Patnaik ,  Wenlin Shao ,  Michael Shultz ,  Ritesh Tichkule ,  Ruben A Tommasi ,  Brian Vash ,  Ping Wang ,  Travis Stams
Affiliations
  • 1. Novartis Institutes for Biomedical Research, 100 Technology Square & 250 Massachusetts Avenue, Cambridge, MA 02139, USA. [email protected]
PMID: 21723733 DOI: 10.1016/j.bmc.2011.06.030
Abstract

Herein we report the discovery of a family of novel yet simple, amino-acid derived class I HDAC inhibitors that demonstrate isoform selectivity via access to the internal acetate release channel. Isoform selectivity criteria is discussed on the basis of X-ray crystallography and molecular modeling of these novel inhibitors bound to HDAC8, potentially revealing insights into the mechanism of enzymatic function through novel structural features revealed at the atomic level.