TY - JOUR
T1 - Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy
AU - Pobbati, Ajaybabu V.
AU - Han, Xiao
AU - Hung, Alvin W.
AU - Weiguang, Seetoh
AU - Huda, Nur
AU - Chen, Guo Ying
AU - Kang, CongBao
AU - Chia, Cheng San Brian
AU - Luo, Xuelian
AU - Hong, Wanjin
AU - Poulsen, Anders
N1 - Funding Information:
We thank Xiangyu Ouyang for performing preliminary experiments for this study, Diana R. Tomchick for help in structure refinement, and Liu Chen Ying for the stable MCF10A cells. This work is financially supported by the Agency for Science, Technology, and Research (A∗STAR), Singapore , and NIH/NIGMS R01GM107415 (to X.L.). X.H. was partially supported by China Scholarship Council . We thank A∗STAR JCO grant No. 1231B015 for G.Y.C.'s postdoctoral fellowship support. The US DOE under contract DE-AC02-06CH11357 supported the use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source.
Publisher Copyright:
© 2015 Elsevier Ltd All rights reserved.
PY - 2015/11/3
Y1 - 2015/11/3
N2 - 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.
AB - 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.
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U2 - 10.1016/j.str.2015.09.009
DO - 10.1016/j.str.2015.09.009
M3 - Article
C2 - 26592798
AN - SCOPUS:84946121238
SN - 0969-2126
VL - 23
SP - 2076
EP - 2086
JO - Structure
JF - Structure
IS - 11
ER -