High-throughput screening to identify modulators of PKD2 function

National Center For Advancing Translational Sciences

Investigators

Abstract

The NCATS Early Translation Branch (ETB) hosts a broad and comprehensive program for the discovery of drug candidates directed towards rare diseases and pharmacological tools to probe the function of the human genome. ETB conducts research to understand the underlying principles driving the translation of basic research discoveries into tangible improvements in human health. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in transmembrane proteins PKD1 (PC1) or PKD2 (PC2). PC1 and PC2 subunits form a cation channel at the plasma membrane, and function can be disrupted by disease-causing mutations. During this period, the collaborative team performed molecular modeling and virtual screening to identify PC1/PC2 activators. Compounds were tested in a high-throughput calcium flux assay using several engineered cell models expressing PKD2 variants. Hits are under further investigation in orthogonal assays in collaborator's lab.