High-Throughput Synthetic Platform for Natural Product Analog Libraries

Summary Background: In small molecule drug development, researchers typically develop biased libraries in which all members share a particular characteristic, such as an ability to interact with a particular target ligand or structural features designed to mimic a particular aspect of a class of natural compounds. For example, a number of libraries have been designed to mimic one or more features of natural peptides. Although these libraries have provided reliable synthetic strategies for compounds possessing specific core functionalities, none have achieved the complexity of structure found in natural products. Complex natural products commonly contain several different functionalities and are often rich in stereochemical diversity. It is also very likely that natural products alone will not provide the hypothetical "complete" set of small molecules that would allow the functions of all proteins as well as their individual domains to be determined. Researchers in the lab of Professor Stuart have overcome these problems with a unique synthetic system that can recapitulate not only the diversity seen in natural products, but also mimic their biological function in vivo.

Invention: A novel, solid-support split-pool synthetic platform that allows for high-throughput production of small molecule libraries. The system utilizes epoxyol and isonicotinamide based templates (which are synthesized in four steps or fewer) to yield more than 2,000,000 complex and highly diverse libraries of compounds. Classes of compounds synthesized with this method can be based on the structure of existing natural products, such as a hormone, receptor, and enzymes. Importantly, these natural product analogs retain their biological function in cell based assays. For example, several compounds in a pool activated a TGF-b responsive reporter gene in a stably transfected mink lung cell line.

Advantages: The functional groups generated from this method are displayed in a radial array, which unlike many polymers or chains of peptides, enables diversification in all directions. This adds to the complexity of the compounds and provides them with a greater likelihood of interacting with biological molecules. There is also a minimal need to employ protecting groups during the synthesis of the scaffold structures and combinatorial libraries.

Applications Commercial Applications: Libraries of compounds are to be utilized in cell-based assays, such as proliferation assays, for the discovery of lead compounds in the treatment and prevention of disease. Generated libraries are also perfect candidates for printing on glass slides to form small molecule arrays (please see Harvard invention 1633 ''Small Molecule Printing'') for drug discovery efforts.

Market: The treatment and prevention of all disease indications.

Publications: Derek S. Tan, Michael A. Foley, Matthew D. Shair, Stuart L. Schreiber. Stereoselective Synthesis of Over Two Million Compounds Having Structural Features Both Reminiscent of Natural Products and Compatible with Miniaturized Cell-Based Assays J. Am. Chem Soc. 1998, 120, 8565-8566.

Derek S. Tan, Michael A. Foley, Brent R. Stockwell, Matthew D. Shair, Stuart L. Schreiber. Synthesis and Preliminary Evaluation of a Library of Polycyclic Small Molecules for Use in Chemical Genetic Assays'', J. Am. Chem. Soc. 1999, 121, 9073-9087

Inventor(s): Schreiber, Stuart L.

Type of Offer: Licensing

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