Research Projects
Our group is dedicated to advancing the field of chemical biology and drug discovery through cutting-edge research. Our work focuses on understanding the complex cellular processes involved in cell signaling and the myriad of molecular interactions that drive them.
New lipid-targeting drugs for human diseases
Many cell signaling proteins, including those critically involved in cancer and neurodegenerative diseases, interact with membrane lipids. We have shown that the cellular activity of these proteins can be potently and specifically blocked by inhibiting their lipid-protein interaction (LPI), Since LPI sites of these proteins are highly variable, they represent attractive targets for developing highly specific drugs. We have recently made breakthroughs in LPI drug discovery by overcoming major conceptual and technical challenges. In a pilot study, we successfully generated a first-in-class small molecule LPI-targeting kinase inhibitor (WC36) for Syk kinase, which plays a key role in acute myeloid leukemia (AML) (Nature Chemical Biology, 2023). Because WC36 blocks lipid binding of the SH2 domain of Syk, it inhibits both kinase activity and SH2 domain-mediated scaffolding activity of Syk. Due to this unique inhibitory activity, WC36 not only potently and specifically blocks the growth of AML cells but also eliminates those cells that have acquired resistance to conventional Syk inhibitors. Further, AML cells cannot develop resistance to WC36, demonstrating the potential of LPI inhibitors as resistance-proof anti-cancer agents. We are currently applying this new technology to developing novel LPI-targeting drugs for diverse human cancers, neurodegenerative diseases, auto-immune diseases, and aging-related diseases.
Lipids as site-specific regulators of cellular processes and regulation and new biomarkers for human diseases
Lipids are essential components of cells that serve as cellular building blocks, energy sources, and dynamic regulatory molecules. Thus, reprogrammed lipid metabolism and aberrant lipid production have been linked to diverse human diseases, including cancer. Since cellular functions of lipids depend on their subcellular location and local concentration, spatiotemporally resolved lipid quantification is essential for full understanding of lipid-mediated cellular processes. Our innovative in situ quantitative lipid imaging technology (Nature Chemistry, 2011; Nature Chemical Biology, 2017; Molecular Cell, 2018) has not only demonstrated high-resolution cellular spatiotemporal dynamics of various lipids but also helped us discover their new cellular function in health and disease. We continue to develop fluorescence-based ratiometric sensors for simultaneous and quantitative imaging of lipids, lipid-protein interaction, and membrane dynamics in diverse live cells and tissues, including patient-derived samples, to elucidate the complex mechanisms of lipid-mediated cell regulation, develop lipids as biomarkers, and identify new targets for drug discovery. We are also developing new chemical biology tools that allow spatiotemporally specific manipulation of lipid actions in live cells.
Multi-talented cholesterol: A rising star in cancer and neurodegenerative diseases
Cholesterol is a major lipid component of the mammalian plasma membrane and its involvement in cardiovascular diseases is well documented. More recently, cholesterol has been linked to numerous human cancers and neurodegenerative diseases, most notably Alzheimer’s disease, but the underlying mechanisms are poorly understood. We recently discovered that cholesterol directly and specifically activates cell signaling proteins, which leads to cell growth and proliferation (Nature Communications, 2012, 2014). Using our ratiometric cholesterol sensors and site-specific cholesterol modulation system, we also discovered that spatiotemporally specific enrichment of cholesterol is crucial for its cellular regulatory function (Nature Chemical Biology, 2017). Furthermore, cancer cells maintain cell type-specific elvated local cholesterol levels that drive cancer progression and also serve as new cancer biomarkers. Based on these exciting new discoveries, we are currently developing new cholesterol-targeting LPI inhibitors for various human cancers, including breast cancer and colorectal cancer. The same approach is also being applied to the development of novel therapy for Alzheimer’s disease and autoimmune diseases.
Other Projects
Our other on-going projects include:
The study of roles of lipids in aging and cell death to improve the quality of life
​
The study of roles of various lipids in phosphoinositide 3-kinase (PI3K) signaling pathways to find new drugs for cancer and other metabolic diseases
​
Developing new methodologies for quantifying cellular membrane protein-lipid interactions
​
Investigating nanoparticle-cell interaction for next-generation nanomedicine
​
Understanding the roles of lipids in gene regulation.
Our Collaborators
The following is the partial list of our current and past collaborators
-
Drs. Barry Honig & Diana Murray, Columbia University, Computational study of lipid-protein interaction and lipid-mediated protein-protein interaction
-
Dr. You-Me Kim, POSTECH, Korea, SH2 domains in immune cell signaling
-
Dr. Daesung Lee, UIC, Fluorophore development
-
Dr. Vladmir Gevorgyan, UIC, Small molecule library for membrane-protein modulation
-
Dr. Irena Levitan, UIC, Regulation of ion channels by cholesterol Dr. Justin Lorieau, UIC, NMR study of SH2 domains
-
Dr. Xiaojing Yang, UIC, X-ray crystallographic study of lipid binding domain
-
Drs. Forbes Porter (NIH)/Kevin Francis (Sanford Research) Cholesterol in Wnt signaling
-
Dr. Jill Weimer, Sanford Research, Regulation of PIP2 signaling
-
Dr. Miriam Rafailovich, Stony Brook University, Nanoparticle-membrane interaction
-
Dr. Akihiro Kusumi, Kyoto University, Single molecule study of lipid-protein interaction
-
Dr. Inhwan Hwang, POSTECH, Korea, Organelle targeting of plant proteins
-
Drs. Robert Winn/Rama Kamesh Bikkavilli, UIC, Cholesterol & cancer
-
Dr. Sungho Ryu, POSTECH, Korea, SH2 domains in cell signaling
-
Dr. Jin-Kwan Han, POSTECH, Korea, Cholesterol in Wnt signaling
-
Dr. Anjen Chenn, UIC, Cholesterol regulation of cell diversity in Sonic Hedgehog Medulloblastoma
-
Dr. Min Goo Lee, Yonsei University, Korea, Regulation of chloride channels by cholesterol