Development of Drugs that Modify CNS Innate Immunity for the Treatment of Multiple Sclerosis

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PROJECT SUMMARY Pathology driven by resident cells in the central nervous system (CNS) such as astrocytes and microglia plays an important role in multiple sclerosis (MS), particularly for its progressive stage which is eventually achieved by most MS patients. However, no drugs are available for the modulation astrocyte and microglia pathogenic activities. We developed an in vitro assay to identify compounds that modulate astrocyte pathogenic activities. These studies identified compound A-38, an inhibitor of the Erythropoietin-producing hepatocellular carcinoma receptor B3 (EphB3), as a suppressor of astrocyte pathogenic activities and, consequently, as a lead therapeutic compound for progressive MS (PMS). Moreover, our data suggest that microglia-driven EphB3 signaling in astrocytes promotes CNS inflammation and neurodegeneration. Ephrin receptors are known to participate in CNS development, however our findings define a novel role for EphB3 in CNS inflammation and identify it as potential target for therapeutic intervention. We hypothesize that EphB3 kinase inhibition will provide an efficacious therapeutic approach for PMS, and potentially other neurologic diseases. Thus, we propose to develop new A-38 analogs to treat PMS. Our Specific Aims are: SPECIFIC AIM 1: OPTIMIZATION AND IN VITRO EVALUATION OF EPHB3 KINASE INHIBITORS. We will design, synthesize and evaluate the properties of up to 150 analogs of A-38. The goal of these studies is to optimize the potency and kinase selectivity of new analogs of A-38, while maintaining good drug-like properties and brain exposure following oral delivery. During the R61 phase of this project, we will integrate iterative structure-activity relationship (SAR) studies and structure based drug design to optimize A-38 potency and kinase selectivity, while maintaining good drug-like properties. We will first evaluate A-38 analogs for EphB3 activity and for selectivity in EphB2 EphB4, and EphA4 kinase assays. Promising compounds will advance to phenotypic assays to identify those molecules that modulate astrocyte pathogenic activities. Compounds of interest will then be characterized in drug-like property assays to select leading compounds for PO PK studies. At the end of the R61 phase of this project we expect to identify a lead EphB3 inhibitor and 1-2 back-ups suitable for advancement into in vivo efficacy testing in the R33 phase. SPECIFIC AIM 2: EVALUATION OF LEAD COMPOUND(S) IN PMS PRE-CLINICAL MODELS. During the R33 phase of this project, we will evaluate the lead EphB3 inhibitor and 1-2 back-ups in the NOD EAE and cuprizone-induced murine pre-clinical models which recapitulate several aspects of PMS. We will evaluate the effects of the compounds on disease development, CNS inflammation, axonal loss and demyelination, as determined by histopathology, flow cytometry and gene expression analyses. In summary, this project will identify a novel EphB3 inhibitor with drug-like properties suitable for development as a candidate therapeutic for PMS and other neurologic diseases with NIH and/or industry support.