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

  • Structure. 2015 Nov 3;23(11):2076-86. doi: 10.1016/j.str.2015.09.009.
Ajaybabu V Pobbati  1 ,  Xiao Han  2 ,  Alvin W Hung  3 ,  Seetoh Weiguang  3 ,  Nur Huda  3 ,  Guo-Ying Chen  3 ,  CongBao Kang  3 ,  Cheng San Brian Chia  3 ,  Xuelian Luo  4 ,  Wanjin Hong  5 ,  Anders Poulsen  6
Affiliations
  • 1. Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Singapore 138673, Singapore. Electronic address: [email protected].
  • 2. Key Laboratory for Molecular Enzymology & Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China; Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
  • 3. Experimental Therapeutics Centre, A(∗)STAR, 31 Biopolis Way, #3-01, Singapore 138669, Singapore.
  • 4. Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA. Electronic address: [email protected].
  • 5. Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Singapore 138673, Singapore.
  • 6. Experimental Therapeutics Centre, A(∗)STAR, 31 Biopolis Way, #3-01, Singapore 138669, Singapore. Electronic address: [email protected].
PMID: 26592798 DOI: 10.1016/j.str.2015.09.009
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.

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