S79: Thailandepsins: Novel Bacterial Natural Products with Potent Histone Deacetylase Inhibition Activities and Promising Anticancer Activities

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 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 and the related spiruchostatins in Pseudomonas sp. 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. Enzyme assays show that thailandepsins are potent HDAC inhibitors as FK228 but the inhibition profiles are different. 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 new 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.