The Kim lab research lies at the interface between chemistry and biology. Specifically, the Kim lab focuses on the development and biological/pharmacological characterization of small molecule inhibitors targeting the proteasome-ubiquitin pathway. There are three main topics under current investigation:
1) Investigation of the roles of the immunoproteasome in cancer: The immunoproteasome, an alternative form of the constitutive proteasome, is highly expressed in some solid and hematologic cancers and may play an important role in cancer cell proliferation and survival. However, the immunoproteasome remains largely untapped for drug discovery, and the biology of the immunoproteasome is poorly understood. The goals of our research thus attempt to address these two major deficits. To examine the biology of the proteasome, we develop and utilize small molecule probes to investigate the role of the immunoproteasome in cancer models. These probes are also essential for our investigation of the chemotherapeutic potential of an immunoproteasome-targeting approach. Recently, we have developed a small molecule (UK-101) that selectively inhibits catalytically active LMP2, a major catalytic subunit of the immunoproteasome. We are also working towards the development of fluorescently labeled UK-101, which can be used as a non-invasive diagnostic tool.
While we are already at the forefront of developing immunoproteasome probes, we aim to become a world-class chemical biology lab in this exciting field. Currently, we are the only one supported by the NIH for the investigation of immunoproteasome functions in cancer in the country.
2) Targeted protein degradation: The PROTAC approach: In the era of systemic proteomics, temporal and spatial control of protein function has become very important in the investigation of complex biological processes in vitro and in vivo. While manipulation of protein expression at the DNA or RNA level has provided a powerful tool to study protein function, widespread applications of these techniques are somewhat limited by the lack of temporal and spatial control. Our goal is to study protein functions using small molecule modulators, which overcome many limitations of a genetic approach.
Specifically, the Kim lab is one of the pioneering laboratories in the development of a targeted protein degradation strategy employing small molecules called PROTACs. These molecules couple a ligand for a target protein with a degradation signal using a linker. The binding of both a protein of interest and the cell’s degradation machinery to the PROTAC results in the ubiquitination and degradation of the protein. PROTACs can be used as molecular probes for functional studies as well as therapeutic agents to destroy disease-promoting proteins. Our current research efforts are focused on refinement of the PROTAC design strategy for in vivo applications.
3) Design and synthesis of chemical probes for use in target identification, validation and in vivo studies: The Kim lab is also focusing on chemical synthesis of biologically active natural products and their synthetic and semi-synthetic analogs for the modes of action studies. The ultimate goals are to understand cellular pathways and to discover new therapeutic approaches for clinical applications.