Discovery of Chemical Probes and Therapeutic Leads, Phase 2

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PROJECT SUMMARY The goal of the parental COBRE award, entitled Discovery of Chemical Probes and Therapeutic Leads, is to develop chemical approaches for probing biology, to discover and apply new chemical biological tools for the study of disease-associated biological pathways, and to understand the interactions between small molecules and their biological targets using computational approaches. In this supplement award application, we propose to develop probes and inhibitors and use these new tools to study the fundamental biochemical properties of ADAM9, a cell-surface metalloproteinase that is a biomarker and a potential therapeutic target for multiple human diseases. Aim 1 of this application (led by Dr. Wei) will be focused on developing sensitive and selective fluorescent peptide substrates for ADAM9, which are currently unavailable. These peptide substrates are necessary for high-throughput screens to identify ADAM9 inhibitors, and for generating biosensors to detect endogenous ADAM9 activity in animal and clinical samples as a biomarker. Aim 2 (led by Dr. Schmitz) will investigate the molecular basis of ADAM9-inhibitor interactions by using an ADAM9 inhibitor that we recently identified. This information is crucial for guiding future identification and optimization of ADAM9 inhibitors. In Aim 3 (led by Dr. Langhans), we will test the feasibility of identifying new ADAM9 inhibitors by conducting a medium-throughput screen with a library containing thousands of compounds. Hits identified in this screen will serve as leads for further optimization to develop potent and selective ADAM9 inhibitors for research and clinical purposes. The proposed study will leverage the unique and complementary skill set of each co-project leader: Dr. Wei is an experienced researcher specializing in metalloproteinase biochemistry and cell biology, Dr. Schmitz is a structural biologist focusing on protease structure-function relationship, and Dr. Langhans, the acting director of the High-Throughput Screen Core Facility at Nemours Children’s Hospital, will contribute her expertise in drug screen. The collaboration will be highly synergistic, as extensive interactions among the three research groups are anticipated for each aim. At the completion of this project, we expect to submit a multi-PI R01 application using the data generated from this study to continue and deepen our collaboration. In conclusion, the proposed collaborative research will have a long-term and transformative impact on understanding the pathology of the related diseases and developing new drugs to treat these diseases.