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

Journal: Structure (London, England : 1993) 2016;23(11):2076-86

PMID: 26592798

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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.

Address: Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Singapore 138673, Singapore. Electronic address: [email protected].; 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.; Experimental Therapeutics Centre, A(∗)STAR, 31 Biopolis Way, #3-01, Singapore 138669, Singapore.; Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA. Electronic address: [email protected].; Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Singapore 138673, Singapore.; Experimental Therapeutics Centre, A(∗)STAR, 31 Biopolis Way, #3-01, Singapore 138669, Singapore. Electronic address: [email protected].

DOI: 10.1016/j.str.2015.09.009

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MeSH Terms: Amino Acid Sequence, Anti-Inflammatory Agents, Non-Steroidal, Antineoplastic Agents, Binding Sites, DNA-Binding Proteins, HEK293 Cells, Humans, Molecular Docking Simulation, Molecular Sequence Data, Protein Binding, TEA Domain Transcription Factors, Transcription Factors