High Throughput Screening for Biased Agonists of the TSH Receptor that Activate the Beta-arrestin pathway

National Center For Advancing Translational Sciences

Investigators

Abstract

The main goal of this project is to develop a potent and selective small molecule TSHR agonist, with biased signaling profile. During this period, the most promising hits from high-throughput screening were identified and followed up with medicinal chemistry and several series of analogs were synthesized. Candidates with attractive activity profiles were pursued with medicinal chemistry to synthesize a series of new analogs, which were advanced for testing in a TSHR overexpressing cell line to determine beta-Arrestin 1 signaling. Pharamcokinetics of the most potent, selective and metabolically stable molecules were carried out. The optimized lead molecule is under evaluation in efficacy mouse models of osteoporosis.