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.

Revista medico-chirurgicala a Societatii de Medici si Naturalisti din Iasi

[New therapeutic strategies in bronchial asthma].

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Author: Goţia, Stela ; Hermeziu, B

Bronchial asthma becomes one of the most frequent respiratory diseases of the childhood. Progresses of the last decade did not interfere with long term prognosis of the disease. New therapeutic researches try to stop the chronic inflammatory respiratory mechanism: cytokines, leukotrienes, transcription factors, IgE. Some of the new drugs are still only experimental--cytokines antagonists, transcription factors inhibitors, adhesin antibodies, other close to clinical use--new corticosteroids, leukotrienes antagonists, anti IgE antibodies. The new therapeutics methods will be used among the classical drugs and will improve the quality of the patients' life.

100 Deals associated with TEA domain transcription factors inhibitors (BridGene )

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	Bridgene Biosciences, Inc.	-

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