Department of Biological Sciences
MC 2406
work:+1 212-854-2948
fax:+1 212-854-3293
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We are using chemical tools to define the interconnected signaling networks underlying cancer and neurodegeneration. Our approach is to perform high-throughput screens with small organic molecules to identify compounds and proteins that act as critical regulators of disease processes. We then define the molecular functions of these critical regulators using the tools of chemical synthesis, protein biochemistry and molecular cell biology.
In this "chemical genetic" approach, small organic molecules that bind directly to proteins are used to alter protein function. This unbiased, discovery-based strategy enables the dissection of signaling pathways in mammalian cells, which are otherwise not amenable to such systematic genetic-like analyses. Potential research projects include synthesizing chemical libraries, identifying the protein targets of novel compounds we have discovered, developing and executing high-throughput assays, creating novel photoaffinity reagents and fluorescent sensors and defining protein ligation events associated with disease proteins.
Our approach to understanding the function of oncoproteins uses synthetic lethal screens to identify small molecules that selectively kill tumor cells expressing specific oncoproteins. Such selectively lethal compounds can target the designated oncoprotein itself, or other proteins in an oncoprotein-linked signaling network. We recently described a novel compound, derived from a combinatorial library, that selectively kills tumorigenic cells expressing both the RASV12 and Small T (ST) oncoproteins. We observed that this new compound, which we named erastin, kills tumorigenic cells without activating apoptosis, which is surprising given the fact that most antitumor agents act by initiating apoptosis. We seek to define the mode of cell death initiated by erastin and the specific proteins that erastin interacts with.
We are also developing new collections of small molecules; for example, via the synthesis of small-molecule inhibitors of E3 ubiquitin ligases, which are components of the ubiquitin-degradation pathway, and determining whether such inhibitors restore tumor suppressor levels and functions in cancer cells. This strategy will provide a framework from which to develop small molecule inhibitors of many critical E3 ubiquitin ligases with relevance to cancer and neurodegeneration.
Finally, we are creating new fluorescent sensors to monitor protein modification events in cells. Such modifications include the covalent coupling of small ubiquitin-like proteins (UBLs) to larger target proteins via specific enzymes. We are developing a series of UBL-derived fluorescent, photoaffinity reagents that will enable determination of protein ligation events that occur on disease-related proteins. These probes will define the role of specific protein ligation events in oncogenic and neurodegenerative processes.
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