SBIR Phase II: Developing a Platform for Multiplexed Drug Profiling Using Yeast Synthetic Agglutination

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is to develop a platform technology for discovering molecular glues. Many illnesses, including cancers, autoimmune diseases, and neurological diseases, can be treated by controlling the activity or abundance of specific proteins in the cell. However, many proteins cannot be targeted by traditional drugs. Instead, pharmaceutical companies are now using a new strategy to hijack the cell’s native quality control pathways and degrade proteins to control their abundance rather than their activity. This approach has been validated as a powerful therapeutic strategy, but significant challenges remain for discovering molecular glues. The proposed platform for molecular glue discovery is expected to have a major commercial and societal impact by conducting high-throughput screening. This Small Business Innovation Research (SBIR) Phase II project proposes to advance the development of a novel platform for discovering molecular glues, or drugs that function by agonizing protein-protein interactions. This platform combines the throughput of a cell-based assay with the accuracy of a bioanalytical technique by linking yeast haploid mating efficiency to the affinity of proteins displayed on the cells' surfaces. Initial results demonstrate that next generation sequencing of diploid cells can be used to simultaneously measure the affinity of many protein-protein interactions with high accuracy and correctly determine the effect of well-characterized small molecules that inhibit or enhance particular protein-protein interactions. Additionally, the platform is functional in a 96-well plate format, which is important for compatibility with standard high-throughput screening workflows. The primary goals of this project are to improve the sensitivity of the platform for the detection of molecular glues that induce a weak protein-protein interaction, reduce the per-well screening cost by improving assay efficiency, and incorporate new proteins into the platform and validate their function with existing small-molecules. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.