Department of Chemistry

Professor Hong's research focuses on using chemical tools to understand the signaling pathways underlying cell and developmental biology.

Determining the cellular function of a protein generally requires a means to alter its activity. The most common way to doing so is indirect, involving the use of inactivating (e.g. deletion or knock-out) or activating (e.g. oncogenic) mutations of the genes encoding the protein of interest. This genetic approach has been widely used in biology and is powerful in that it can readily identify gene products involved in a specific process and then mutate the encoding gene with complete specificity within a complex cellular context. However, there are situations in which small molecules might be more useful. First, in many cases, small molecule can be applied to study a process of interest in a wide range of organisms, whereas a genetic approach logically demands that the desired genetic modification has to be regenerated every time the experimental system is switched. Second, most mutations are not conditional; therefore, the activity of the protein of interest cannot be turned on or off at will. This lack of temporal control substantially limits the use of genetic approaches towards the study of dynamic processes. By contrast, small molecules can directly change the way proteins work, thereby representing tools with a uniquely high temporal resolution, capable of dissecting dynamic cellular processes. Within in the past several years, a new field has emerged at the interface between cell biology and synthetic organic chemistry that promises to systemize the discovery of small organic compounds as tools to probe biochemical pathways. The term ‘Chemical Genomics/Genetics’ has been coined for an approach that uses small organic molecules as probes to study protein functions in cultured cells or whole organisms. The use of small molecules to affect biological phenomena has made a significant impact in diverse areas of biology. Our broad and long-term goal is to identify and functionally characterize novel genes/proteins that are active in fundamental biological phenomena with chemical genomics approach.

The research foci of our laboratory are:

1. Development of New Synthetic Methodology: We will design and develop unique and efficient synthetic strategies which will enable rapid access to molecular complexity and structural diversity. These new methodologies will be useful for the synthesis of complex natural products.
2. Natural Product Synthesis and Study of Mode of Action: We will explore the modes of action of biologically active natural products in order to investigate intracellular signaling pathways and identify novel targets for drug design.
3. Construction of Small Molecule Library and Establishment of High-Throughput Cell-Based Assay: With the advent of combinatorial chemistry and other synthetic technologies, it is feasible to prepare large collections of synthetic organic molecules. These libraries are useful in providing molecules that can be used to probe the relevant biological pathways. Since the ability to identify small molecule ligands for any protein of interest has far-reaching implications, both for the elucidation of protein function and for the development of novel pharmaceuticals, the availability of efficient methods for screening libraries of compounds become imperative. In spite of much progress in the field, those methods developed so far need further modification. We will develop more efficient and reliable methods for screening these compounds in cultured cells or whole organisms.
4. Development of Novel Technology for Chemical Genomics: Chemical genomics is currently limited by a major technical hurdle in pursuit of the ultimate goal of identifying the molecular targets of hit compounds in the most physiologically relevant settings possible (i.e., in vivo) once their phenotypic activity has been confirmed. We are interested in developing efficient and reliable methods for the identification of molecular target(s).

The research activities described above will use a combination of synthetic organic chemistry and cell biology to synthesize and screen small molecule modulators of signaling pathways and to identify the molecular targets of the hit compounds. Through these multidisciplinary approaches, the cellular components and molecular events that embody cell differentiation, integrin signaling, vesicle trafficking, epithelial–mesenchymal transition (EMT), and cell-cell interaction will be systematically explored. Compounds employed in these studies could also advance the development of novel therapeutics for the treatment of human diseases including cancers.