The primary focus of this application is to develop more potent and less toxic, isoform-selective histone deacetylase (HDAC) inhibitors (HDACi) for use as anti-myeloma and anti-cancer drug candidates, biological tools for investigation of specific functions of individual HDACs and extension of this chemical class beyond antineoplastic indications. Specifically, we plan to optimize the structures of macrocyclic peptide analogues of largazole, and related naturally occurring HDAC inhibitors for HDAC class- selectivity by altering the amino acid sequence and zinc-binding functionality in accord with parameters derived from crystal structures of the target enzymes deploying additional computational and empiric insights. Analogues will be assayed for inhibitory activity against HDACs 1-11 in the laboratories of co- investigator Dr. James E. Bradner at the Broad Institute of Harvard-MIT and the Dana-Farber Cancer Institute and Dr. James R. Berenson at the Institute for Myeloma and Bone Cancer Research. Assessment of the safety and pharmacodynamic effect will be performed by Prof. Douglas Thamm and co- workers at the CSU College of Veterinary Medicine and Biomedical Sciences. Insight from the results of these assays will guide further alterations of the candidate structures. A computational co-investigator, Prof. Olaf Wiest, at the University of Notre Dame, will deploy homology model-based docking studies to further guide the design and optimization of new synthetic HDACi's. We have developed scaleable solution-phase syntheses of the known, highly potent natural HDACi's largazole and FK228 as well as the corresponding peptide isosteres and numerous synthetic analogs of these potent and naturally occurring HDACi's. Structural diversity within the analogs will be explored by varying three parameters: (a) amino acid sequence and constitution;(b) macrocycle size;and (c) zinc-binding arms. Particularly potent and/or isoform-selective macrocyclic peptide inhibitors that are produced by this approach will be targeted for re-synthesis as the corresponding depsipeptide congeners and profiled for potency and specificity in biochemical and cellular assays. Select isoform-specific analogs will be evaluated for in vivo tolerability and antineoplastic activity.

Public Health Relevance

The purpose of this application is to develop new classes of drugs that target a new and exciting biochemical target recently recognized as being essential to the cancer cell cycle. The new target is a class of enzymes that exist inside all cells called histone deacetylase enzymes (HDAC's). Our multidisciplinary project brings together synthetic organic chemistry, computational modeling, chemical biology and clinical evaluation of potential inhibitors of HDAC's.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA152314-04
Application #
8510596
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2010-09-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$287,684
Indirect Cost
$44,733
Name
Colorado State University-Fort Collins
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Chen, Kai; Zhang, Xiaoxiao; Wu, Yun-Dong et al. (2014) Inhibition and mechanism of HDAC8 revisited. J Am Chem Soc 136:11636-43
Guerra-Bubb, Jennifer M; Bowers, Albert A; Smith, William B et al. (2013) Synthesis and HDAC inhibitory activity of isosteric thiazoline-oxazole largazole analogs. Bioorg Med Chem Lett 23:6025-8
Chen, Kai; Xu, Liping; Wiest, Olaf (2013) Computational exploration of zinc binding groups for HDAC inhibition. J Org Chem 78:5051-5
Ghosh, Sajal K; Perrine, Susan P; Williams, Robert M et al. (2012) Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents. Blood 119:1008-17