Abstract P2169: Identification Of Pro-adhesive Drugs By A Novel High-throughput Approach

Abstract

Defective cell-cell adhesion contributes to the patho-mechanism of various diseases. In line with this, a mouse model recently developed by our group demonstrate that loss of cell-cell adhesion is an important initial step leading to Arrhythmogenic Cardiomyopathy (ACM), a disease which presents with severe arrhythmia, ventricular fibrosis and impaired cardiac function. Derived from the central role of defective cell-cell adhesion for the patho-mechanism, we here aim to identify new compounds, which restore intercellular adhesion and could serve as potential therapeutics. To screen a high number of agents, we developed an adhesion-based high-throughput approach by adapting a standard cell-cell dissociation assay to 96-well plate format including establishment of an automated acquisition and analysis pipeline. To model loss of intercellular adhesion, cells deficient for the desmosomal adhesion molecule desmoglein-2 were used. After establishing settings to sensitively detect changes in cell-cell adhesion, this method was applied to screen a library of 1946 FDA-approved drugs in three concentrations. Several new compounds strengthening intercellular adhesion were identified in addition to known pro-adhesive drugs, confirming the robustness of our assay. The increased adhesiveness of selected top hits was confirmed in cells expressing ACM patient mutations. In conclusion, we here developed an adhesion-based high-throughput approach capable of identifying adhesion modulators which have the potential to be used as therapeutics for diseases with defective desmosomal adhesion such as ACM.