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Discovery of a new class of reversible TEA domain transcription factor inhibitors with a novel binding mode
The TEA domain (TEAD) transcription factor forms a transcription co-activation complex with the key downstream effector of the Hippo pathway, YAP/TAZ. TEAD-YAP controls the expression of Hippo-responsive genes involved in cell proliferation, development, and tumorigenesis. Hyperactivation of TEAD-YA...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9728997/ https://www.ncbi.nlm.nih.gov/pubmed/36398861 http://dx.doi.org/10.7554/eLife.80210 |
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author | Hu, Lu Sun, Yang Liu, Shun Erb, Hannah Singh, Alka Mao, Junhao Luo, Xuelian Wu, Xu |
author_facet | Hu, Lu Sun, Yang Liu, Shun Erb, Hannah Singh, Alka Mao, Junhao Luo, Xuelian Wu, Xu |
author_sort | Hu, Lu |
collection | PubMed |
description | The TEA domain (TEAD) transcription factor forms a transcription co-activation complex with the key downstream effector of the Hippo pathway, YAP/TAZ. TEAD-YAP controls the expression of Hippo-responsive genes involved in cell proliferation, development, and tumorigenesis. Hyperactivation of TEAD-YAP activities is observed in many human cancers and is associated with cancer cell proliferation, survival, and immune evasion. Therefore, targeting the TEAD-YAP complex has emerged as an attractive therapeutic approach. We previously reported that the mammalian TEAD transcription factors (TEAD1–4) possess auto-palmitoylation activities and contain an evolutionarily conserved palmitate-binding pocket (PBP), which allows small-molecule modulation. Since then, several reversible and irreversible inhibitors have been reported by binding to PBP. Here, we report a new class of TEAD inhibitors with a novel binding mode. Representative analog TM2 shows potent inhibition of TEAD auto-palmitoylation both in vitro and in cells. Surprisingly, the co-crystal structure of the human TEAD2 YAP-binding domain (YBD) in complex with TM2 reveals that TM2 adopts an unexpected binding mode by occupying not only the hydrophobic PBP, but also a new side binding pocket formed by hydrophilic residues. RNA-seq analysis shows that TM2 potently and specifically suppresses TEAD-YAP transcriptional activities. Consistently, TM2 exhibits strong antiproliferation effects as a single agent or in combination with a MEK inhibitor in YAP-dependent cancer cells. These findings establish TM2 as a promising small-molecule inhibitor against TEAD-YAP activities and provide new insights for designing novel TEAD inhibitors with enhanced selectivity and potency. |
format | Online Article Text |
id | pubmed-9728997 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-97289972022-12-08 Discovery of a new class of reversible TEA domain transcription factor inhibitors with a novel binding mode Hu, Lu Sun, Yang Liu, Shun Erb, Hannah Singh, Alka Mao, Junhao Luo, Xuelian Wu, Xu eLife Biochemistry and Chemical Biology The TEA domain (TEAD) transcription factor forms a transcription co-activation complex with the key downstream effector of the Hippo pathway, YAP/TAZ. TEAD-YAP controls the expression of Hippo-responsive genes involved in cell proliferation, development, and tumorigenesis. Hyperactivation of TEAD-YAP activities is observed in many human cancers and is associated with cancer cell proliferation, survival, and immune evasion. Therefore, targeting the TEAD-YAP complex has emerged as an attractive therapeutic approach. We previously reported that the mammalian TEAD transcription factors (TEAD1–4) possess auto-palmitoylation activities and contain an evolutionarily conserved palmitate-binding pocket (PBP), which allows small-molecule modulation. Since then, several reversible and irreversible inhibitors have been reported by binding to PBP. Here, we report a new class of TEAD inhibitors with a novel binding mode. Representative analog TM2 shows potent inhibition of TEAD auto-palmitoylation both in vitro and in cells. Surprisingly, the co-crystal structure of the human TEAD2 YAP-binding domain (YBD) in complex with TM2 reveals that TM2 adopts an unexpected binding mode by occupying not only the hydrophobic PBP, but also a new side binding pocket formed by hydrophilic residues. RNA-seq analysis shows that TM2 potently and specifically suppresses TEAD-YAP transcriptional activities. Consistently, TM2 exhibits strong antiproliferation effects as a single agent or in combination with a MEK inhibitor in YAP-dependent cancer cells. These findings establish TM2 as a promising small-molecule inhibitor against TEAD-YAP activities and provide new insights for designing novel TEAD inhibitors with enhanced selectivity and potency. eLife Sciences Publications, Ltd 2022-11-18 /pmc/articles/PMC9728997/ /pubmed/36398861 http://dx.doi.org/10.7554/eLife.80210 Text en © 2022, Hu, Sun, Liu et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Hu, Lu Sun, Yang Liu, Shun Erb, Hannah Singh, Alka Mao, Junhao Luo, Xuelian Wu, Xu Discovery of a new class of reversible TEA domain transcription factor inhibitors with a novel binding mode |
title | Discovery of a new class of reversible TEA domain transcription factor inhibitors with a novel binding mode |
title_full | Discovery of a new class of reversible TEA domain transcription factor inhibitors with a novel binding mode |
title_fullStr | Discovery of a new class of reversible TEA domain transcription factor inhibitors with a novel binding mode |
title_full_unstemmed | Discovery of a new class of reversible TEA domain transcription factor inhibitors with a novel binding mode |
title_short | Discovery of a new class of reversible TEA domain transcription factor inhibitors with a novel binding mode |
title_sort | discovery of a new class of reversible tea domain transcription factor inhibitors with a novel binding mode |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9728997/ https://www.ncbi.nlm.nih.gov/pubmed/36398861 http://dx.doi.org/10.7554/eLife.80210 |
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