Targeting Protein-Protein Interactions in the Autophagy Pathway

Autophagy has been implicated as a potential target for cancer therapy due to its role in homeostasis and the development of resistance to chemotherapeutics. Previous efforts to target autophagy in cancer have focused on disrupting lysosome function or inhibiting enzymes that initiate autophagy, but these strategies have led to defects in other cellular pathways, thus limiting clinical applications. An alternative approach is to target key protein-to-protein interactions that are required for the initiation of autophagy to provide more selective inhibitors. Our group has recently discovered small molecules that disrupt autophagy-specific protein-to-protein interactions, and the goal of this project is to optimize these molecules to study the efficacy of selective autophagy inhibition to treat chemotherapeutic-resistant cancers with poor survival rates. 

Discovery of Small-Molecule Autophagy Modulators with Novel Mechanisms of Action

Using a combination of phenotypic assays and subsequent target identification and validation, our group has been able to identify small molecules that modulate the autophagy pathway through mechanisms that have not been previously studied. Our recently published work highlights how this approach could provide novel strategies for therapeutic development to treat a variety of diseases. The current goal of this project is to study how the newly identified targets and mechanisms regulate the autophagy pathway to improve disease phenotypes.

Discovery, Synthesis, and Evaluation of Natural Products and Natural Product–Inspired Compounds

Natural products have a rich history of medical relevance and success as therapeutics. One of the most challenging, yet appealing, aspects for this field is the development of synthetic routes to access these complex molecular scaffolds quickly and efficiently. Our group develops microwave-assisted organic synthesis approaches to help accelerate access to natural product core scaffolds. We have recently used a systematic diversity-oriented synthesis approach to prepare analogs of the flavonoid class of natural products that have increased stereochemical complexity and unnatural appendages or substitution patterns in less than six synthetic steps. Analogs of these flavonoid scaffolds have been prepared and these molecules were screened in a diverse set of biological assays, including the Cell Painting Assay, to assess performance diversity. The assays also help to better understand what type of molecules should be included in screening collections to reduce performance redundancy and to discover novel chemical probes for complex biological processes and historically challenging disease targets. Novel molecules accessed through this methodology enable the evaluation of the biological activities of molecules that are inspired by natural products but are not limited by organism production levels, natural selection for bioactivity or synthetic accessibility. Our current goals in this area include the synthesis of natural products and natural product–inspired compounds with interesting biological activities to generate probes for target identification and evaluation in disease-relevant assays.