Download MendeleyTargeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy.
Pobbati, A.V., Han, X., Hung, A.W., Weiguang, S., Huda, N., Chen, G.Y., Kang, C., Chia, C.S., Luo, X., Hong, W., Poulsen, A.(2015) Structure 23: 2076-2086
- PubMed: 26592798
- DOI: https://doi.org/10.1016/j.str.2015.09.009
- Primary Citation of Related Structures:
5DQ8, 5DQE - PubMed Abstract:
The human TEAD family of transcription factors (TEAD1-4) is required for YAP-mediated transcription in the Hippo pathway. Hyperactivation of TEAD's co-activator YAP contributes to tissue overgrowth and human cancers, suggesting that pharmacological interference of TEAD-YAP activity may be an effective strategy for anticancer therapy. Here we report the discovery of a central pocket in the YAP-binding domain (YBD) of TEAD that is targetable by small-molecule inhibitors. Our X-ray crystallography studies reveal that flufenamic acid, a non-steroidal anti-inflammatory drug (NSAID), binds to the central pocket of TEAD2 YBD. Our biochemical and functional analyses further demonstrate that binding of NSAIDs to TEAD inhibits TEAD-YAP-dependent transcription, cell migration, and proliferation, indicating that the central pocket is important for TEAD function. Therefore, our studies discover a novel way of targeting TEAD transcription factors and set the stage for therapeutic development of specific TEAD-YAP inhibitors against human cancers.
Organizational Affiliation:
Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Singapore 138673, Singapore. Electronic address: [email protected].
