(1310-C) High-throughput pathway screening and target deconvolution of novel oncogenic YAP/TAZ signaling pathway inhibitors
Tuesday, February 6, 2024
12:00 PM – 1:00 PM EST
Location: Exhibit Halls AB
Abstract: A pathway high-throughput screen of 3.8 million compounds by using a cellular YAP1/TAZ-dependent luciferase reporter was performed in a 4µl miniaturized 1536-well plate format. The in vitro hit compound 1 was identified in this screening campaign as a potent inhibitor of YAP1/TAZ activation. Target deconvolution studies, including cellular thermal shift assays and CRISPR/Cas9-KO screens, elucidated PGGT1B, a subunit of the geranylgeranyltransferase-I (GGTase-I) complex, as the direct target of YAP1/TAZ pathway inhibitors. GGTase-I inhibitors blocked the activation of Rho-GTPases at the cell membrane, leading to subsequent inactivation of YAP1/TAZ.