Pathway Assay Matrix for Drug Discovery in Angiogenesis

DESCRIPTION (provided by applicant): The long term goal of this research proposal is to develop drugs for the treatment of diabetic retinopathies (DR) and age related macular degeneration (AMD). Current early phase drug discovery programs are focused on a single target in the target validation and lead identification stage. The target is studied and bioactive molecules are identified assuming that the function of the target is unchanged when isolated from the context of cellular regulation and dynamics. This proposal outlines a research plan to test small chemical libraries in a novel assay platform that probes multiplexed targets in a pathway with the goal of identify better lead molecules for drug development. This assay platform is called the pathway assay matrix (PAM). The proposed pathway assay matrix would monitor multiple target nodes simultaneously using different assay readouts optimized for performance. This approach does not define the target up front; rather, it lets the compound's effect on the pathway determine the best target. It is also proposed that the PAM would yield data that better predicts performance of the molecule in in vivo models. Phase I feasibility will be tested in an angiogenesis signaling model that monitors key pathway nodes in a VEGF-dependent manner. Known and novel library of potential inhibitors will be tested to determine if the pathway based approach clusters bioactivity of molecules and better predicts the performance of the molecule in an in vivo animal model. Bioinformatics requirements will also be developed during Phase I. The best molecule will show dose dependent potency and high selectivity for a pathway with good potency correlation in the in vivo system. Phase II of the project will involve expansion of the number of assay nodes in the matrix to include additional pathways. Miniaturization of the format will enable screening of larger compound libraries to identify novel inhibitors of angiogenesis for treatment of DR and AMD. This will become the platform base for the discovery of novel drugs for treatment of pro and anti-angiogenic diseases.