Design, synthesis, biological evaluation, and structural characterization of potent histone deacetylase inhibitors based on cyclic alpha/beta-tetrapeptide architectures.
Histone deacetylases (HDACs) are a family of enzymes found in bacteria, fungi, plants, and animals that profoundly affect cellular function by catalyzing the removal of acetyl groups from -N-acetylated lysine residues of various protein substrates including histones, transcription factors, alpha-tubulin, and nuclear importers. Although the precise roles of HDAC isoforms in cellular function are not yet completely understood, inhibition of HDAC activity has emerged as a promising approach for reversing the aberrant epigenetic states associated with cancer and other chronic diseases. Potent new isoform-selective HDAC inhibitors would therefore help expand our understanding of the HDAC enzymes and represent attractive lead compounds for drug design, especially if combined with high-resolution structural analyses of such inhibitors to shed light on the three-dimensional pharmacophoric features necessary for the future design of more potent and selective compounds. Here we present structural and functional analyses of a series of beta-amino-acid-containing HDAC inhibitors inspired by cyclic tetrapeptide natural products. To survey a diverse ensemble of pharmacophoric configurations, we systematically varied the position of the beta-amino acid, amino acid chirality, functionalization of the Zn(2+)-coordinating amino acid side chain, and alkylation of the backbone amide nitrogen atoms around the macrocycle. In many cases, the compounds were a single conformation in solution and exhibited potent activities against a number of HDAC isoforms as well as effective antiproliferative and cytotoxic activities against human tumor cells. High-resolution NMR solution structures were determined for a selection of the inhibitors, providing a useful means of correlating detailed structural information with potency. The structure-based approach described here is expected to furnish valuable insights toward the future design of more selective HDAC inhibitors.
Montero
Ana
A
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Beierle
John M
JM
Olsen
Christian A
CA
Ghadiri
M Reza
MR
D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D009842:Oligopeptides; D006655:Histone Deacetylases