Diversity-Oriented Synthesis and Rational Drug Design for Chemical Biology and Drug Discovery Research

Research in the Tan Lab focuses on synthetic organic chemistry and its applications to current challenges in chemical biology and drug discovery.

In the area of rational drug design, we are developing small molecule inhibitors that target adenylation enzymes, which are involved in a wide range of biological processes implicated in numerous human diseases. We use mechanistic and structural information about individual targets of interest to design small molecule inhibitors. Among these are novel antibiotics that inhibit bacterial biosynthesis of siderophores, menaquinone, and phenolic glycolipids. Semisynthetic protein-based inhibitors of eukaryotic E1 activating enzymes have also revealed striking enzyme remodeling during the conjugation of ubiquitin and other ubiquitin-like modifers to target proteins. We leverage synergistic multidisciplinary collaborations with biologists in our Tri-Institutional Research program and at other institutions to pursue these efforts.

We are also engaged in a complementary program in diversity-oriented synthesis, in which we are developing new synthetic routes and strategies to access small molecules containing key structural motifs found in biologically active natural products. These efforts provide exciting opportunities to develop new synthetic methodologies and insights into chemical reactivity. Efficient, flexible synthetic routes are used to generate natural product-based libraries that access regions of chemical space that are not addressed by conventional drug-like libraries. These natural product-based libraries are being screened against a wide range of promising new therapeutic targets through collaborations with other labs in the Tri-Institutional Research Program, the Broad Institute, and the NIH Molecular Libraries Initiative. More information about these projects is available below.
 

Key Review Articles

• Rational Drug Design of Adenylation Enzyme Inhibitors
  Adenylation enzymes mediate a variety of important bacterial and eukaryotic pathways. We are using rational drug design to develop sulfonyladenosine-based inhibitors of adenylation enzymes as new antibiotics and chemical probes.
• Ring Expansion Approaches to Macrocycle Synthesis
  Macrocycles are an attractive class of molecules for use in biological screening. While smaller molecules have been used to bind in enzyme active sites and other protein pockets, larger molecules such as macrocycles may be useful for affecting protein-protein interactions involving large surface areas… .
• Stereoselective Diversity-Oriented Synthesis of Spiroketals
  Spiroketals are privileged substructures found in numerous natural products with diverse biological activities. We are developing stereoselective diversity-oriented synthesis routes to provide spiroketal libraries with comprehensive stereochemical diversity for screening against a wide range of biological targets.
• Diversity-Oriented Synthesis of Multiscaffold Alkaloid Libraries
  An amazing range of rigid, densely functionalized polycyclic compounds are formed from simple precursors during the biosynthesis of alkaloids and terpenoids. To access such structures, we are using a related diversity-oriented synthesis strategy to generate multiscaffold polycyclic libraries from a small set of simple precursors.