The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project is that for the first time, drug developers will have access to a platform to measure global changes to the set of proteins that bind and regulate the human genome. With this tool in hand, pharmaceutical researchers will be able to target molecular pathways previously inaccessible for drug development against Gene Regulatory Protein (GRP)-regulated cancer, neurological, and other conditions. The beneficial effects of drug-based therapies to treat cancers such as multiple myeloma (MM), small cell lung carcinoma, and neurological cancers will improve health outcomes: In the USA alone, about 1.8 million new cancer cases are diagnosed every year. Millions of people will benefit if any drug targeting the function of GRPs is identified using this technology. This Small Business Innovation Research (SBIR) Phase I project converts technology from a manual bench application into a high-throughput platform. This project will implement a quantitative proteomics-based drug discovery platform that quantifies the effects of small-molecules on the GRP proteome in a diversity of cell and tissue types. Despite their relevance in health and disease, GRPs have been largely considered undruggable for several reasons, including the lack of knowledge of small-molecule pockets and high degrees of intrinsic protein disorder, which both make biochemical study challenging and full structural characterization almost impossible. This project will tackle this problem by removing the need for GRP biochemical isolation via implementing a methodology where the GRP proteome is studied in situ. This method employs nuclear fractionation followed by GRP isolation and characterization, resulting in a platform that can inform the effects of drug compounds on the chromatin-bound proteome. This project will build the first database that links in a statistically-robust manner compounds to their effects on the genome-bound proteome, with links to laboratory measurements (i.e., high-resolution mass spectrometry). The curated data will include both presence of drug/proteome interactions and false and/or positive discovery rates.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.
