Discovery of potent and selective histone deacetylase inhibitors via focused combinatorial libraries of cyclic alpha3beta-tetrapeptides.

ABSTRACT: Histone deacetylase (HDAC) inhibitors are powerful tools in understanding epigenetic regulation and have proven especially promising for the treatment of various cancers, but the discovery of potent, isoform-selective HDAC inhibitors has been a major challenge. We recently developed a cyclic alpha(3)beta-tetrapeptide scaffold for the preparation of HDAC inhibitors with novel selectivity profiles ( J. Am. Chem. Soc. 2009 , 131 , 3033 ). In this study, we elaborate this scaffold with respect to side chain diversity by synthesizing one-bead-one-compound combinatorial libraries of cyclic tetrapeptide analogues and applying two generations of these focused libraries to the discovery of potent HDAC ligands using a convenient screening platform. Our studies led to the first HDAC6-selective cyclic

SUBMITTER: Olsen CA 

PROVIDER: S-EPMC2788660 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature