Derek S. Tan, Ph.D.Tri-Institutional Associate Professor
Memorial Sloan-Kettering Cancer Center
Program in Molecular Pharmacology and Chemistry
Genome sequencing efforts and an increasingly molecular understanding of biology have revealed myriad new biological targets of both fundamental and potential therapeutic interest. Small molecules are extremely powerful tools for dissecting the functions of and evaluating the therapeutic potential of these targets. However, the identification of new, highly specific small molecule ligands remains a major challenge in chemical biology and drug discovery. To address this problem, Dr. Tan's lab uses a two-pronged approach involving diversity-oriented synthesis and rational design, both of which leverage insights from natural products. They leverage multidisciplinary collaborations with biologists to evaluate the molecules they synthesize.
Dr. Tan's lab is synthesizing libraries of small molecules that incorporate key bioactive structural elements of natural products to guide ligand design for targets for which no structural or mechanistic information is available. Because existing methods for synthesizing these substructures are often unsuitable for diversity-oriented synthesis, the lab develops new chemical strategies to access these molecules. These libraries are being used in high throughput screens to identify new small molecule ligands for a variety of biological targets.
Dr. Tan's lab also uses natural products as invaluable starting points for ligand design, in conjunction with structural and mechanistic information about selected biological targets. In particular, his lab has developed several sulfonyladenosine-based inhibitors of adenylation enzymes that play key roles in microbial pathogenesis and eukaryotic signal transduction. These compounds have provided new insights into the underlying mechanisms of these processes and serve as lead compounds for the development of novel antibiotics and anticancer agents.
- Wurst, J.M. et al. Hydrogen-bonding catalysis and inhibition by simple solvents in the stereoselective kinetic epoxide-opening spirocyclization of glycal epoxides to form spiroketals. J. Am. Chem. Soc. 133, 7916–7925 (2011).
- Moura-Letts, G. et al. Solid-phase synthesis and chemical space analysis of a 190-membered alkaloid/terpenoid-like library. Proc. Natl. Acad. Sci. U.S.A. 108, 6745–6750 (2011).
- Olsen, S.K. et al. Active site remodelling accompanies thioester bond formation in the SUMO E1. Nature 463, 906–912 (2010).