Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy

Ajaybabu V. Pobbati, Xiao Han, Alvin W. Hung, Seetoh Weiguang, Nur Huda, Guo Ying Chen, CongBao Kang, Cheng San Brian Chia, Xuelian Luo, Wanjin Hong, Anders Poulsen

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)2076-2086
Number of pages11
JournalStructure
Volume23
Issue number11
DOIs
StatePublished - Nov 3 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

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    Pobbati, A. V., Han, X., Hung, A. W., Weiguang, S., Huda, N., Chen, G. Y., Kang, C., Chia, C. S. B., Luo, X., Hong, W., & Poulsen, A. (2015). Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy. Structure, 23(11), 2076-2086. https://doi.org/10.1016/j.str.2015.09.009