Monday, August 2, 2010
Pacific Concourse (Hyatt Regency San Francisco)
Epigenetic abnormalities participate with genetic mutations to cause cancer; consequently epigenetic intervention of cancer has emerged as a promising avenue toward cancer therapy, with three synthetic compounds approved in the past few years by the US Food and Drug Administration (FDA) for clinical use. FK228, a naturally produced histone deacetylase (HDAC) inhibitor which has entered into nearly 40 clinical trials and exhibited positive effect against many types of cancer, was the latest one 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 engineered HDAC inhibitors as anticancer lead compounds. Our studies of the biosynthesis of FK228 and related spiruchostatins have led to the discovery of two new structural analogs, thailandepsins A and B. HDAC inhibition assays indicated that thailandepsins have different inhibition profile than that of FK228. NCI-60 anticancer screening showed that thailandepsins have potent inhibitory and lethal activity against a significant number of human cancer cell lines. We seek further collaborations to address the detailed pharmacological effects of thailandepsins on cancer biology. With access to three homologous biosynthetic pathways that collectively produce five structural analogs, we have now established an excellent platform for combinatorial biosynthesis of a library of FK228-family “un-natural” natural products for anticancer drug discovery and development.