Natural products have represented a prominent source of cancer drugs and valuable chemical probes for investigating cancer-associated biological processes. The structural complexity of these molecules, however, constitute a major hurdle toward their expeditious synthesis and manipulation, as required for their development into probes and therapeutics. Building upon our pioneering contributions in the development of chemo-enzymatic strategies for late-stage functionalization and diversification of complex natural products, this project will generate large libraries of novel and unique natural-product-like compounds as a readily accessible source of small-molecule agents for both basic cancer ...

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Natural products have represented a prominent source of cancer drugs and valuable chemical probes for investigating cancer-associated biological processes. The structural complexity of these molecules, however, constitute a major hurdle toward their expeditious synthesis and manipulation, as required for their development into probes and therapeutics. Building upon our pioneering contributions in the development of chemo-enzymatic strategies for late-stage functionalization and diversification of complex natural products, this project will generate large libraries of novel and unique natural-product-like compounds as a readily accessible source of small-molecule agents for both basic cancer research and anticancer drug development. The mechanism of action of lead compounds with diversified anticancer profile will be elucidated to unveil new targets for cancer therapy. This project will also develop macrocyclic peptides for selective targeting and modulation of protein-protein interactions implicated in the Hippo cell signaling pathway, which is misregulated in many human cancers. Using a powerful display system for high-throughput screening and target-driven selection of vast and diverse libraries of macrocyclic peptides, we will develop chemical agents capable of suppressing signaling at different critical points of the Hippo pathway, enabling first-time assessment of their therapeutic potential for cancer treatment. Finally, we will implement an innovative platform for phenotype-driven discovery of anticancer macrocyclic peptides, which will furnish a complementary strategy to the discovery of novel and currently unknown targets and mechanisms for killing cancer cells. These natural-product-like libraries, molecular discovery platforms, and the UT Dallas Center for Reaction Discovery & High-Throughout Synthesis will provide key resources to the cancer community in Texas for supporting basic cancer research and development of novel cancer therapeutics.

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