Epigenetic abnormalities participate with genetic mutations to cause cancer;consequently epigenetic intervention of cancer has emerged as a promising avenue toward cancer therapy. Selective inhibition of histone deacetylases (HDACs) by small molecules often leads to a cascade of chromatin remodeling, tumor suppressor gene reactivation, apoptosis, and regression of cancer. First-in-class HDAC inhibitor on the market, Zolinza (by Merck) - a synthetic compound, was approved for the treatment of cutaneous T-cell lymphoma in late 2006. FK228 represents a small family of rare natural products with unique structural properties, potent HDAC inhibition activities, good anticancer therapeutic index, but also certain levels of undesirable cytotoxicity. Our studies of the biosynthesis of FK228 and spiruchostatins have led to the discovery of thailandepsins A and B, two new naturally produced FK228-family analogs with better HDAC inhibition activities and predicted anticancer activities currently being evaluated at the US National Cancer Institute (NCI) Developmental Therapeutics Program (DTP). Our working hypothesis is that targeted discovery from prioritized microorganisms and biosynthetic engineering of parallel metabolic pathways could lead to the acquisition of additional FK228 analogs with better anticancer therapeutic index. Thus, the overall goal of this application is to explore naturally produced and metabolically engineered HDAC inhibitors as anticancer lead compounds. To achieve this goal we will pursue the following studies: Firstly, we will characterize new genes and new pathways involved in the biosynthesis of FK228-family natural products in selected bacterial species. This study will provide important guidance for downstream engineered biosynthesis efforts. Secondly, we will discover and engineer a library of new FK228- family analogs by means of targeted bioprospecting, genome mining, simple gene deletion or insertion, complex genetic manipulation, combinatorial biosynthesis, precursor-directed mutasynthesis, de novo biosynthesis and engineering in heterologous hosts, and chemoenzymatic synthesis. Finally, we will identify new HDAC inhibitors and new anticancer lead compounds through in vitro enzyme inhibition assays and collaborative screening against the NCI's 60 cancer cell lines.

Public Health Relevance

Selective inhibition of histone deacetylases (HDACs) has emerged as a promising avenue toward cancer therapy. We propose to discover, engineer and screen for new HDAC inhibitors with improved anticancer activities and reduced cytotoxicities. This research will generate new anticancer lead compounds for further evaluation toward clinical applications.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA152212-05
Application #
8734896
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2010-08-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Texas
Department
Pharmacology
Type
Graduate Schools
DUNS #
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Liu, Xiangyang; Xie, Feng; Doughty, Leah B et al. (2018) Genomics-guided discovery of a new and significantly better source of anticancer natural drug FK228. Synth Syst Biotechnol 3:268-274
Liu, Xiangyang; Zhu, Hui; Biswas, Sreya et al. (2016) Improved production of cytotoxic thailanstatins A and D through metabolic engineering of Burkholderia thailandensis MSMB43 and pilot scale fermentation. Synth Syst Biotechnol 1:34-38
Bermudez, Jaclyn Y; Webber, Hannah C; Patel, Gaurang C et al. (2016) HDAC Inhibitor-Mediated Epigenetic Regulation of Glaucoma-Associated TGF?2 in the Trabecular Meshwork. Invest Ophthalmol Vis Sci 57:3698-707
Xiao, Kai; Li, Yuan-Pei; Wang, Cheng et al. (2015) Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of breast cancer. Biomaterials 67:183-93
Shah, Gopitkumar R; Wesener, Shane R; Cheng, Yi-Qiang (2015) Engineered Production of Tryprostatins in E. coli through Reconstitution of a Partial ftm Biosynthetic Gene Cluster from Aspergillus sp. Jacobs J Biotechnol Bioeng 2:
Robers, Matthew B; Dart, Melanie L; Woodroofe, Carolyn C et al. (2015) Target engagement and drug residence time can be observed in living cells with BRET. Nat Commun 6:10091
Potharla, Vishwakanth Y; Wang, Cheng; Cheng, Yi-Qiang (2014) Identification and characterization of the spiruchostatin biosynthetic gene cluster enable yield improvement by overexpressing a transcriptional activator. J Ind Microbiol Biotechnol 41:1457-65
Weinlander, Eric; Somnay, Yash; Harrison, April D et al. (2014) The novel histone deacetylase inhibitor thailandepsin A inhibits anaplastic thyroid cancer growth. J Surg Res 190:191-7
Li, Jie; Wang, Cheng; Zhang, Zhi-Min et al. (2014) The structural basis of an NADP?-independent dithiol oxidase in FK228 biosynthesis. Sci Rep 4:4145
Liu, Xiangyang; Cheng, Yi-Qiang (2014) Genome-guided discovery of diverse natural products from Burkholderia sp. J Ind Microbiol Biotechnol 41:275-84

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