Abstract PR07: Targeting the Hippo-YAP pathway with small-molecule compounds

The Hippo-YAP pathway is involved in the regulation of cell proliferation, survival, and cell migration. It functions normally to control tissue regeneration and homeostasis and limit organ size/shape. Genetic alterations of pathway components resulting in YAP activation have been reported in a variety of human malignancies. YAP activity is also linked to resistance to targeted therapies and cancer relapse. Through high-throughput phenotypic screens, we have identified novel classes of small-molecule compounds that target the Hippo-YAP pathway. Using different assays, we determined whether the screen hits specifically inhibit YAP-TEAD transcription activity and examined their effects on YAP phosphorylation, YAP nuclear and cytoplasmic localization, and YAP-TEAD interaction. To map the target points in the Hippo pathway, we analyzed the effects of the compounds in cells deficient for various pathway components. Lead optimization resulted in highly potent inhibitors that block YAP-TEAD transcription activity at single-digit nM, and we have identified the molecular targets of some chemical series. In all, we have discovered different classes of pathway inhibitors: 1) compounds that induce YAP phosphorylation and cytoplasmic translocation, 2) compounds that induce YAP cytoplasmic translocation without affecting its phosphorylation, and 3) compounds that work in the nucleus to block YAP-TEAD transcription activity without affecting YAP phosphorylation or nuclear localization. Examples of a few classes will be presented to illustrate that we now have a way to target the Hippo-YAP pathway that thus far has been undruggable and is dysregulated in many cancers and critically associated with targeted therapy resistance. This abstract is also being presented as Poster B15. Citation Format: Tracy T. Tang, Andrei W. Konradi, Ying Feng, Xiao Peng, Sofie Qiao, Leonard Post. Targeting the Hippo-YAP pathway with small-molecule compounds [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr PR07.