Abstract 4867: Using a fragment based approach for the identification of TEAD S3 pocket binders

Abstract

YAP1 and TEAD are transcriptional regulators involved in organ size control and cell proliferation. Aberrant activation of YAP1 has been reported for multiple tumor types and inhibiting the interaction of YAP1 with its partner protein TEAD is thought to be a means of targeting aberrant YAP1 activity. In order to identify small molecule inhibitors of YAP1 interaction with TEAD, we have performed a fragment-based-screening looking for ligands binding to TEAD at its interface with YAP1 (TEAD pocket S3). We have employed three techniques for fragment screening (NMR, SPR, DSF) and have cross tested positive hits identified by one technique with the respective orthogonal method. Using this strategy on Sanofi proprietary fragment libraries, three different fragment series have been identified. X-Ray co-structures with TEAD have been obtained for all three fragment series confirming binding to the S3 pocket of TEAD. Binding mode determination by X-Ray crystallography has set the stage for subsequent fragment optimization. Citation Format: Laure Delarbre, Olivier Venier, Iris Valtingojer, Jacques Houtmann, Maryse Lowinski, Annick Parent, Françoise Bégassat, Angelique Lasbleiz, Catherine Seys, Philippe Bombart, Laurent Debussche, Alexey Rak. Using a fragment based approach for the identification of TEAD S3 pocket binders [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4867.