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, Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy, Structure, Volume 23, Issue 11, 3 November 2015, Pages 2076-2086, ISSN 0969-2126, http://dx.doi.org/10.1016/j.str.2015.09.009.
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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