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Advances in genomics have revealed myriad new potential therapeutic targets. However, existing small-molecule drugs address only a small set of approximately 550 protein targets encoded in the human genome. Efforts to expand have been thwarted by a heavy focus on a correspondingly narrow range of complementary chemical structures in drug discovery. To address this problem, Tan’s lab leverages insights from natural products in diversity-oriented synthesis and rational drug design to identify novel small-molecule ligands for a variety of targets. They leverage multidisciplinary collaborations with biologists to evaluate the molecules they synthesize to probe complex biological processes and pursue new therapeutic opportunities in cancer and infectious diseases.

In the area of diversity-oriented synthesis, Tan’s lab uses structural motifs found in biologically active natural products as starting points for library design. At the core of these efforts is the development of new synthetic routes to provide flexible, efficient, systematic access to these structures. The resulting libraries access distinct regions of chemical space compared to conventional drug-like libraries and are screened against a wide range of biological targets.

In the area of rational drug design, Tan’s lab designs natural product-based sulfonyladenosine inhibitors of adenylation enzymes, a mechanistic superfamily implicated in a wide range of biological processes. Leveraging structural and mechanistic information, they have developed new antibiotic lead compounds that inhibit enzymes required for bacterial virulence and semisynthetic protein inhibitors of ubiquitin-family E1 activating enzymes that have revealed dramatic active site remodeling during catalysis.

Tan is the director in the Tri-Institutional Ph.D. Program in Chemical Biology based at Memorial Sloan Kettering Cancer Center.