Development of the Dominant Rotor Technology for Drug Discovery

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This proposal leverages the recently developed technology aimed at conformation-activity studies and rarely visited conformations of complex rings. The primary focus is on macrocycles that are primarily composed of natural amino acid building blocks. While cyclic peptides have received a tremendous amount of attention over the years, their structures are not ideally suited for the development of biological probes and therapeutic agents. Our new method, recently reported in Nature Chemistry, provides a solution to this challenge. Paraza Pharma and Genentech are the two partner organizations on this application.Genentech is a large biotechnology company with a rich history of excellence in peptide science and peptide-based drugs. Genentech Inc. has invested in the Yudin group as an industry partner with the goal to advance the understanding of peptide science. Genentech Inc. aims to use the technology developed in the Yudin lab to access new tools towards the synthesis of conformationally-controlled peptide-based inhibitors of protein-protein interactions. Genentech's involvement would help the Yudin lab to develop a library of structurally diverse macrocycles with unique dominant rotor sub-structures, and assess their chemical, physical, and biological properties in a much shorter amount of time compared to what is typically expected in an academic setting. Paraza Pharma is a chemical sciences-based company with aims towards streamlining the drug discovery processes. The company will use Yudin's chemistry in order to incorporate imidazopyridines into dominant rotors, deploy their exciting benzocyclobutane amino acids, and guide us through construction of macrocyclic kinase inhibitors. Paraza will provide scientific expertise in process and analytical development, particularly with regard to the suitability of Yudin's building blocks in synthesis.