We seek to identify novel nonpeptide macrocyclic histone deacetylase (HDAC) inhibitors as a new class of anticancer agents. HDAC inhibitors hold great promise in cancer therapy due to their demonstrated ability to arrest proliferation of nearly all transformed cell types. However, most of these agents are non-selective inhibitors of all HDAC isoforms;and a large number of the identified HDAC inhibitors have not progressed beyond preclinical characterizations. Our hypothesis in this proposal is that substitution of the peptide moiety of a prototypical cyclic- peptide HDAC inhibitor with specific non-peptidyl macrocyclic surrogates will generate a new class of potent HDAC inhibitors with improved therapeutic index. These compounds are anticipated to also possess targeted anti-cancer activity due to selective tissue distribution conferred by the appended macrocyclic moiety. In Preliminary Results a class of macrocyclic hydroxamates has been identified. The goal of this application is to study the molecular mechanisms underlying the in vitro anti-HDAC and anti-tumor activities of these compounds.
Aim 1 is to develop novel nonpeptide macrocyclic HDAC inhibitors. The first step here is to broaden our design approach to include other structurally similar macrocyclic templates in order to create a tool set upon which subsequent structure activity relation (SAR) studies will be based. To guide this effort, we will use molecular docking (AutoDock) to investigate the SAR of the combination of these macrocyclic templates with key HDAC inhibitor pharmacophores.
Aim 2 is to characterize the structural and biochemical requirements for in vitro and whole cell HDAC inhibition. Toward this end, we will profile the anti-HDAC activity of compounds obtained from the priority list generated by the docking experiments using both in vitro HDAC inhibition assay and whole cell activity in human lung cancer cell lines. Moreover, we will evaluate the whole cell mechanism of our potent inhibitors based on intracellular status of p21WAF1/CIP1 and HDAC7 genes, and histone protein acetylation patterns.
Our Aim 3 is to investigate the organ distribution and in vivo efficacy of lead compounds in mice. We will first study compound organ distribution behavior in healthy male Balb/c mice. Compounds displaying lung selective accumulation with good pharmacokinetic parameters will then be advanced to in vivo efficacy studies in Balb/c (nu/nu) mice bearing xenograft models of specific lung cancers. In the longer term, we will identify series of novel HDAC inhibitors that will be advanced to further preclinical/clinical evaluations. Additionally, the proposed studies will yield new insights on the roles of HDACs in the etiology of cancer.

Public Health Relevance

Lung cancer is the leading cause of cancer deaths in the US. Outlined in this proposal is a method that will enable identification of new classes of chemotherapeutic agents that possess lung- selective anti-cancer activity for targeted lung cancer therapy applications. Our proposed approach is expected to lead to chemotherapeutic agents with superior therapeutic indices and will significantly impact patient survival prognosis and positively contribute to human health management.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131217-04
Application #
8298481
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2009-09-25
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$292,322
Indirect Cost
$88,347
Name
Georgia Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
Sodji, Quaovi; Patil, Vishal; Jain, Surendra et al. (2014) The antileishmanial activity of isoforms 6- and 8-selective histone deacetylase inhibitors. Bioorg Med Chem Lett 24:4826-30
Dreaden, Erik C; Raji, Idris O; Austin, Lauren A et al. (2014) P-glycoprotein-dependent trafficking of nanoparticle-drug conjugates. Small 10:1719-23
Gryder, Berkley E; Akbashev, Michelle J; Rood, Michael K et al. (2013) Selectively targeting prostate cancer with antiandrogen equipped histone deacetylase inhibitors. ACS Chem Biol 8:2550-60
Patil, Vishal; Sodji, Quaovi H; Kornacki, James R et al. (2013) 3-Hydroxypyridin-2-thione as novel zinc binding group for selective histone deacetylase inhibition. J Med Chem 56:3492-506
Gryder, Berkley E; Rood, Michael K; Johnson, Kenyetta A et al. (2013) Histone deacetylase inhibitors equipped with estrogen receptor modulation activity. J Med Chem 56:5782-96
Guerrant, William; Patil, Vishal; Canzoneri, Joshua C et al. (2013) Dual-acting histone deacetylase-topoisomerase I inhibitors. Bioorg Med Chem Lett 23:3283-7
Guerrant, William; Patil, Vishal; Canzoneri, Joshua C et al. (2012) Dual targeting of histone deacetylase and topoisomerase II with novel bifunctional inhibitors. J Med Chem 55:1465-77
Gryder, Berkley E; Sodji, Quaovi H; Oyelere, Adegboyega K (2012) Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed. Future Med Chem 4:505-24
Patil, Vishal; Guerrant, William; Chen, Po C et al. (2010) Antimalarial and antileishmanial activities of histone deacetylase inhibitors with triazole-linked cap group. Bioorg Med Chem 18:415-25
Mwakwari, Sandra C; Guerrant, William; Patil, Vishal et al. (2010) Non-peptide macrocyclic histone deacetylase inhibitors derived from tricyclic ketolide skeleton. J Med Chem 53:6100-11

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