Abstract 5418: Thailandepsins: Novel bacterial natural products with potent histone deacetylase inhibition activities and promising anticancer activities
Authors: Wang Cheng , Henkes Leonhard , Doughty Leah B. , He Min , Wang Difei , Meyer-Almes Franz-Josef , Newman David J. , Cheng Yi-Qiang 
Published: June 2012

Epigenetic abnormalities participate with genetic mutations to cause cancer; consequently epigenetic intervention of cancer has emerged as a promising avenue toward cancer therapy, with one synthetic compound verinostat (SAHA, Zolinza® by Merck & Co.) and one natural product FK228 (depsipeptide, romidepsin, Istodax® by Gloucester Pharma) already approved by FDA for the treatment of cutaneous T-cell lymphoma. 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 the related spiruchostatin in Pseudomonas sp. Q71576 have led to the discovery of thailandepsin A and thailandepsin B, two novel natural analogs of FK228 and spiruchostatins, from the culture broth of Burkholderia thailandensis E264. HDAC inhibition assay shows that thailandepsins have as potent inhibitory activities as FK228 toward human HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, HDAC8 and HDAC9; but there is a significant differentiation between FK228 and thailandepsins toward HDAC4, underlining potentially differential anticancer activities. NCI60 anticancer screening shows that thailandepsins possess a broad spectrum of growth inhibition activities, and have reached GI50 for over 90% of the tested cell lines even at the lowest concentration (10-8M) used in the screening. Most interestingly, thailandepsins 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 additional naturally produced HDAC inhibitors that are promising for anticancer drug development. We seek further collaborations to address the detailed pharmacological effects of thailandepsins on cancer biology. In addition, with access to three homologous biosynthetic pathways that collectively produce five structural analogs, we have now established an excellent platform for combinatorial biosynthesis and chemical derivatization of a library of FK228-family “un-natural” natural products for anticancer drug discovery and development. Supports for this research were from the University of Wisconsin-Milwaukee, the US Department of Defense Breast Cancer Research Program and the US National Institute of Health/National Cancer Institute.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5418. doi:10.1158/1538-7445.AM2011-5418