title: Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy.
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.
authors.affiliation: Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Singapore 138673, Singapore. Electronic address: ajaybabuvp@imcb.a-star.edu.sg.
authors.forename: Ajaybabu V
authors.initials: AV
authors.lastname: Pobbati
authors.affiliation: 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.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: Experimental Therapeutics Centre, A(∗)STAR, 31 Biopolis Way, #3-01, Singapore 138669, Singapore.
authors.forename: Alvin W
authors.initials: AW
authors.lastname: Hung
authors.affiliation: Experimental Therapeutics Centre, A(∗)STAR, 31 Biopolis Way, #3-01, Singapore 138669, Singapore.
authors.forename: Seetoh
authors.initials: S
authors.lastname: Weiguang
authors.affiliation: Experimental Therapeutics Centre, A(∗)STAR, 31 Biopolis Way, #3-01, Singapore 138669, Singapore.
authors.forename: Nur
authors.initials: N
authors.lastname: Huda
authors.affiliation: Experimental Therapeutics Centre, A(∗)STAR, 31 Biopolis Way, #3-01, Singapore 138669, Singapore.
authors.forename: Guo-Ying
authors.initials: GY
authors.lastname: Chen
authors.affiliation: Experimental Therapeutics Centre, A(∗)STAR, 31 Biopolis Way, #3-01, Singapore 138669, Singapore.
authors.forename: CongBao
authors.initials: C
authors.lastname: Kang
authors.affiliation: Experimental Therapeutics Centre, A(∗)STAR, 31 Biopolis Way, #3-01, Singapore 138669, Singapore.
authors.forename: Cheng San Brian
authors.initials: CS
authors.lastname: Chia
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA. Electronic address: xuelian.luo@utsouthwestern.edu.
authors.forename: Xuelian
authors.initials: X
authors.lastname: Luo
authors.affiliation: Institute of Molecular and Cell Biology, A(∗)STAR, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.affiliation: Experimental Therapeutics Centre, A(∗)STAR, 31 Biopolis Way, #3-01, Singapore 138669, Singapore. Electronic address: apoulsen@etc.a-star.edu.sg.
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
mesh_terms: D000595:Amino Acid Sequence; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000091262:TEA Domain Transcription Factors; C101205:TEAD2 protein, human; D014157:Transcription Factors