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Program Highlights

As presented at the 2012 ACS Spring Annual Meeting

Platform for Discovery and Development of Histone Deacetylase Inhibitors as Therapeutic Agents Targeting Epigenetics

Yi-Qiang “Eric” Cheng, Associate Professor. Department of Biological Sciences, and Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI, USA

Tel: 414-229-4739; E-mail: ycheng@uwm.edu

ABSTRACT: 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. HDAC inhibitors have thus gained much attention in recent years as a new class of anticancer agents, with one synthetic compound SAHA and one natural product FK228 approved by FDA for clinical use. FK228 represents a small family of natural products, all of which are produced by Gram-negative bacteria, and each of which contains a signature disulfide bond that mediates a novel mode of anticancer action. The overall goal of our research is to explore naturally produced and metabolically or chemically modified histone deacetylase (HDAC) inhibitors as anticancer lead compounds. Our studies of the biosynthesis of FK228 in Chromobacterium violaceum no. 968 and of spiruchostatins in Pseudomonas fluorescens Q71576 revealed two highly homologous biosynthetic pathways that bear yet distinctive features; those studies further led to the discovery of a series of new natural products named thailandepsins A through F from the culture broth of Burkholderia thailandensis E264. Enzyme assays showed that thailandepsins are potent HDAC inhibitors as FK228 but the inhibition profiles are different. NCI60 anticancer screening showed that thailandepsin A possesses a broad spectrum of growth inhibition activities, and has reached GI50 for over 90% of the tested cell lines even at the lowest concentration (10–8M) used in the screening. Most interestingly, thailandepsin A demonstrated differential activities toward certain types of cell lines at TGI and LC50 levels, particularly for those derived from colon, melanoma and renal cancers. Thailandepsins therefore represent new naturally produced HDAC inhibitors that are promising for anticancer drug development.With access to three homologous natural product biosynthetic pathways that collectively produce 10 structural analogues, we have now established an excellent platform for combinatorial biosynthesis and chemical synthesis of a library of HDAC inhibitors for drug discovery and development. We seek academic collaborations to address the detailed pharmacological effects of thailandepsins on cancer biology; we also seek partnership with investors or licensing opportunities with the pharmaceutical industry.