Ph.D.: Boston University, 2005
Postdoc: Harvard University and Broad Institute of Harvard & MIT, 2008
Chemical biology is an emerging field that integrates several related disciplines, such as synthetic organic chemistry, biochemistry, molecular and cellular biology. Chemical biologists use small molecules to perturb and understand a range of biological processes including signaling and cognition, differentiation and reprogramming, pathology and the treatment of diseases. Our research is focused on the development and applications of novel small-molecule probes using highly integrated approaches.
Natural products, resulting from millions of years of evolution, are valuable tools for chemical biologists to study biological processes. Many of these molecules and their structural analogs often prove useful in medical applications. Recently, researchers have been using bioassays to direct isolations of natural products with desired biological activities, such as anti-cancer, anti-bacterial, or antiviral activities. Inpired by the natural products, we plan to develop novel synthetic methodologies and strategies for practical syntheses of biologically active small molecules. In addition, we are also interested in discovering the cellular targets of these molecules, in an effort to understand the underlying mechanisms of their natural existence.
Epigenetics is the study of stable and heritable changes in gene expression or cellular phenotype without affecting the underlying DNA sequence of the organism. Epigenetic regulation has been proven to play a critical role in many biological processes, such as gene expression, embryonic development and genomic reprogramming. Our studies in this area focus on chromatin modifications, especially methylations of histone proteins and DNA. These modifications are closely regulated by a series of enzymes, such as histone lysine demethylases (KDMs) and DNA cytosine hydroxylases (TETs). Small molecules inhibiting HDACs or DNMTs have already been proven useful in clinical trials of cancer therapies. We plan to develop specific small-molecule modulators of these enzymes using both structure-based design and unbiased screening approach. These molecules should complement genetic tools for the elucidation of the critical roles of chromatin-modifying enzymes in biology.
Small Molecules Discovered from HTS
As chemical genetics has proved to be a unique and powerful method to study biology, more and more biologists are interested in pursuing this kind of studies. We have established collaborations with biologists in a variety of areas to discover small-molecules probes with novel biological activities using state-of-the-art high-throughput screening technologies at CU-Boulder HTS core facility. Current efforts in this category include discovering small molecules that:
- prevent degradation of tumor suppressor proteins;
- improve the efficiency of somatic cell reprogramming;
- interfere with bacterial pathogenesis and persistance.
1. A Selective Inhibitor and Probe of the Cellular Functions of Jumonji C Domain-Containing Histone Demethylases. Luo X, Liu Y, Kubicek S, Myllyharju J, Tumber A, Ng S, Che KH, Podoll J, Heightman TD, Oppermann U, Schreiber SL, Wang X* J Am Chem Soc. 2011;133:9451-9456. [link] Highlighted by SciBX. [link]
2. Bio-Inspired Synthesis Yields A Tricyclic Indoline That Selectively Resensitizes MRSA to β-Lactam Antibiotics. Podoll JD, Liu Y, Chang L, Walls S, Wang W, Wang X. Proc Natl Acad Sci USA. 2013;110:15573-15578; doi:10.1073/pnas.1310459110. [link] Highlighted by PNAS[link]; Recommended by Faculty of 1000 [link].