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A chemical biology approach to the modulation of cell fate and cell state

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Our research laboratory uses a chemical biology approach to study cell fate- and cell state-determining processes that play a causative role in the progression of human disease. We have ongoing research programs in areas ranging from the selective induction of endogenous stem cell differentiation to the modulation of immunological response within tumor microenvironments. Using the tools of structural diversity and high throughput phenotype-based discovery, small molecules are identified that selectively induce a desired impact on cell fate (e.g., induced differentiation towards a defined lineage) or cell state (e.g., mitotic catastrophe). Validated hit compounds, demonstrated to function via a novel mechanism, are subjected to parallel structure-activity relationship studies and medicinal chemistry-based optimization, as well as target identification and mechanism of action studies. Potential molecular targets are identified using diverse mass spectrometry-based proteomics approaches involving synthesized photo-activatable affinity probe reagents. Downstream mechanism(s) of action are elucidated using standard cell and molecular biology-based techniques. Our research efforts ultimately result in chemistry-based discovery of novel biological mechanisms and the direct enablement of new drug discovery programs. Using this phenotype-based discovery approach, we have identified novel targets and mechanisms, as well as potential drug candidates, for the treatment of multiple sclerosis and defined cancer cell types. Specifically, we have identified agents that enhance oligodendrocyte differentiation/maturation, as well as molecules that selectively target glioblastoma cancer stem cells and mesenchymal cancers.

This talk is part of the Biological Chemistry Research Interest Group series.

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