Abstract 2200: A rational approach for discovery of inhibitors of YAP-TEAD interaction

The Hippo signalling pathway plays a major role in organ growth regulation and tumorigenesis. By sensing contact inhibition, the central kinase network of the hippo pathway controls nuclear translocation and activity of the YAP transcription factor. Once translocated in the nucleus, YAP interacts with the TEAD family of transcription factors and drives expression of gene involved in cell survival and proliferation. Deregulation of the hippo pathway frequently occurs in cancers and high nuclear expression of YAP has been documented in many tumors including lung, colorectal, ovarian and skin cancers. These data suggest that targeting the hippo pathway is a new therapeutic option for the treatment of a large number of cancers. Several approaches are currently proposed to target the hippo pathway such as inhibition of kinases and GPCRs that are upstream regulators of YAP nuclear translocation. However, because YAP and TEAD are the downstream effectors of the Hippo pathway, we believe that targeting YAP-TEAD interaction is the most promising approach to selectively counteract abnormal activity of the Hippo pathway. We have started a drug discovery program aimed at identifying potent inhibitors of YAP-TEAD interaction, based on a combined FBLD/HTS strategy. Druggability of the TEAD protein was assessed by a fragment screen using NMR and SPR technologies. This approach, conforted by assigned HSQC protein NMR information, provided fragment hits which are used as starting points for the identification of more potent binders. We have also designed a dedicated AlphaScreen assay to validate the ability of our compounds to disrupt the YAP-TEAD interaction. Fifty thousand compounds of the Inventiva9s library were screened using the AlphaScreen. Several hits in the micromolar range were identified and further confirmed using SPR. Hits are currently tested for their ability to disrupt YAP-TEAD interaction in a cellular context with a transactivation assay and for their ability to block tumoral cell proliferation. Citation Format: Claudia Fromond, Laurent Chene, Anne Soude, Martine Barth, Christian Montalbetti, Pierre Broqua. A rational approach for discovery of inhibitors of YAP-TEAD interaction. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2200. doi:10.1158/1538-7445.AM2015-2200