Discovery of a new class of reversible TEA-domain transcription factor inhibitors with a novel binding mode
- Massachusetts General Hospital, United States
- The University of Texas Southwestern Medical Centerh, United States
- University of Massachusetts Medical School, United States
Abstract
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 anti-proliferation 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.
Data availability
The crystal structure of TEAD2 YBD in complex with TM2 has been deposited in the Protein Data Bank with accession codes 8CUH. The raw RNA-seq data of NCI-H226 treated with TM2, K975 and VT103 has been deposited in NCBI GEO and is accessible at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215114.
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Next Generation Sequencing Quantitative Analysis of TEAD Inhibitors in NCI-H226 cellsNCBI Gene Expression Omnibus, GSE215114.
Article and author information
Author details
Funding
National Cancer Institute (R01CA219814)
- Xu Wu
National Cancer Institute (R01CA238270)
- Xu Wu
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK127180)
- Junhao Mao
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK127207)
- Junhao Mao
Welch Foundation (I-1932)
- Xuelian Luo
Antidote Health Foundation for the cure of cancer (postdoc fellowship)
- Lu Hu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Hu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Discovery of a new class of reversible TEA-domain transcription factor inhibitors with a novel binding mode
eLife 11:e80210.
https://doi.org/10.7554/eLife.80210
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