Research

Research in the Lee group focuses on small-molecule drug discovery

1. Synthesis of Biologically Active Natural Products and Derivatives

Natural products have been rich sources for drug discovery. We synthesize biologically active natural products and their derivatives to explore structure-activity relationship (SAR). We investigate the role of the natural products in cellular signal cascades and evaluate the small-molecules pharmacologically. Currently, we are interested in resorcylic acid macrolactones and phenylacetic acid lactones such as pochonin D, curvularins and xestodecalactones. These natural products showed good anti-tumor and/or anti-inflammotory activities by targeting heat-shock protein 90 (Hsp90) and/or unknown target(s).

2.Discovery of Kinase Inhibitors

Kinases play important roles in regulating cellular signaling pathways and have been considered very attractive drug targets. Several small-molecules and antibodies that target kinases have been approved as new drugs in past two-decades. Currently, we make efforts to discover new c-Met and ALK inhibitors by using structure-based drug design. c-Met and ALK have been considered as good gastric and lung cancer targets.

3.Discovery of New Cellular Modulators from Screening of Small-molecule Libraries

We screen small-molecule libraries to identify cellular modulators. Then, we explore their SAR and molecular mechanisms to identify novel targets. Hedgehog signaling regulates self-renewal of stem cells and is involved in the formation of various cancers. We have found new Hedgehog (Hh) signaling antagonists by screening ~10,000 compounds. Currently, we are characterizing the antagonists biologically.

4.Development of Novel Synthetic Methods and Application to Natural Product Synthesis

Intramolecular enolate alkylation strategy has been successfully utilized to stereoselectively synthesize cycloalkanes and medium-sized ether rings by Professor Deukjoon Kim’s group (Seoul National University). In collaboration with Kim group, we are expanding this strategy to stereoselectively synthesize tetrahydropyran, tetrahydrofuran, piperidine and pyrrole rings. Currently, we are applying this strategy to the synthesis of biologically interesting natural products such as (+)-chamuvarinin, (-)-centrolobine and (-)-cassine.