A chemical perspective on the modulation of TEAD transcriptional activities: Recent progress, challenges, and opportunities

Lou, Jianfeng; Lu, Yuhang; Cheng, Jiang; Zhou, Feilong; Yan, Ziqin; Zhang, Daizhou; Meng, Xiangjing; Zhao, Yujun

doi:10.1016/j.ejmech.2022.114684

Cited by 20 publications

(27 citation statements)

References 166 publications

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“…An approach to address this gap in our understanding is to investigate readouts of up and down regulation of Hippo signaling with determination of cell specific transcription employing translating ribosome affinity purification (TRAP) technologies in vivo [36]. As we have previously discussed, these measurements can be combined with proteomic determinations of proteins in the polyribosome/mRNA complexes in cardiac myocytes and various cell types in the micro-environment Development of small molecules modifying the Hippo pathway intended for therapy in cancer provide important information related to the development of agents for use in cardiovascular disorders such as DCM [37,38]. Although we know from human clinical trials that agents such as TRULI1 and XMU-MP-1 have not been approved yet, CinicalTrials.…”

Section: Discussionmentioning

confidence: 99%

The Hippo Signaling Pathway as a Drug Target in Familial Dilated Cardiomyopathy

Wolska

Langa

Solaro³

2022

IJDDP

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Review The Hippo Signaling Pathway as a Drug Target in Familial Dilated Cardiomyopathy Paulina Langa 1, Beata M. Wolska1,2, R. John Solaro1,* 1 Department of Physiology and Biophysics and the Center for Cardiovascular Research,University of Illinois at Chicago, Chicago, IL,USA. 2 Department of Medicine, Division of Cardiology, College of Medicine, University of Illinois at Chicago, Chicago, IL,USA. * Correspondence: solarorj@uic.edu, Tel.: +1 (312)-420-0241, +1(312)-996-8546, Fax: +1 (312) 996-1414 Received: 1 November 2022 Accepted: 24 November 2022 Published: 21 December 2022 Abstract: We focus here on the Hippo pathway in the hierarchical sensing and modulation of the mechanical state of the adult heart in health and disease. The Hippo pathway interrogates the micro-environment of cardiac myocytes providing surveillance of the mechanical state with engagement of signaling pathways critical to homeostasis of cardiac development, remodeling, and function and vulnerable to pathologies. Our discussion centers on Hippo signaling in the altered mechanical state instigated by variants of genes expressing mutant sarcomere proteins that trigger a progression to dilated cardiomyopathy (familial DCM). There is an unmet need for therapies in DCM. Recent progress in the discovery of small molecules that target Hippo signaling and are intended for use in cardiac disorders provides leads for modifying Hippo in DCM. As we emphasize, identifying useful targets in DCM requires in depth understanding of cell specific Hippo signaling in the cardiac micro-environment.

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Section: Discussionmentioning

confidence: 99%

The Hippo Signaling Pathway as a Drug Target in Familial Dilated Cardiomyopathy

Wolska

Langa

Solaro³

2022

IJDDP

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“…15 Therefore, the "hotspot" of the YAP:TEAD interaction is the Ω-loop pocket. Peptides and low-molecular-weight molecules that bind to this region have been described 11,16,17 and ongoing clinical trials should determine their potential use as anticancer agents. Less progress has been made on molecules targeting the α-helix pocket, but a mimetic of the TEAD-binding domain of VGLL4 18 and low-molecular-weight compounds 19 have been described recently.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Different approaches are under evaluation, and several compounds binding to the palmitate/myristate pocket have already entered the clinic. 10,11 Even though some of these compounds have been described as preventing the YAP:TEAD interaction, so far only a few molecules that directly block it have been identified. 10,11 YAP binds to TEAD via three distinct areas: the β-stand, the α-helix and the Ω-loop pockets named accordingly to the secondary structure elements from the YAP TEAD-binding domain (TBD) that interact with them (Figure 1A).…”

Section: ■ Introductionmentioning

confidence: 99%

“…10,11 Even though some of these compounds have been described as preventing the YAP:TEAD interaction, so far only a few molecules that directly block it have been identified. 10,11 YAP binds to TEAD via three distinct areas: the β-stand, the α-helix and the Ω-loop pockets named accordingly to the secondary structure elements from the YAP TEAD-binding domain (TBD) that interact with them (Figure 1A). Since the interactions formed within the β-stand pocket are mainly hydrogen bonds between the main chain amides of TEAD and YAP, 12,13 this interface is a priori not so attractive for drug discovery.…”

Section: ■ Introductionmentioning

confidence: 99%

“…It has also been shown that TEAD can be palmoylated/myristoylated and this posttranslational modification is required for its function. , As different alterations of the Hippo pathway have been identified in human cancers, TEAD is an attractive target for oncology: inhibiting its interaction with YAP is currently being intensively researched. Different approaches are under evaluation, and several compounds binding to the palmitate/myristate pocket have already entered the clinic. , Even though some of these compounds have been described as preventing the YAP:TEAD interaction, so far only a few molecules that directly block it have been identified. , YAP binds to TEAD via three distinct areas: the β-stand, the α-helix and the Ω-loop pockets named accordingly to the secondary structure elements from the YAP TEAD-binding domain (TBD) that interact with them (Figure A). Since the interactions formed within the β-stand pocket are mainly hydrogen bonds between the main chain amides of TEAD and YAP, , this interface is a priori not so attractive for drug discovery.…”

Section: Introductionmentioning

confidence: 99%

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Biochemical and Structural Characterization of a Peptidic Inhibitor of the YAP:TEAD Interaction That Binds to the α-Helix Pocket on TEAD

et al. 2023

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The TEAD transcription factors are the most distal elements of the Hippo pathway, and their transcriptional activity is regulated by several proteins, including YAP. In some cancers, the Hippo pathway is deregulated and inhibitors of the YAP:TEAD interaction are foreseen as new anticancer drugs. The binding of YAP to TEAD is driven by the interaction of an α-helix and an Ω-loop present in its TEAD-binding domain with two distinct pockets at the TEAD surface. Using the mRNA-based display technique to screen a library of in vitro-translated cyclic peptides, we identified a peptide that binds with a nanomolar affinity to TEAD. The X-ray structure of this peptide in complex with TEAD reveals that it interacts with the α-helix pocket. Under our experimental conditions, this peptide can form a ternary complex with TEAD and YAP. Furthermore, combining it with a peptide binding to the Ω-loop pocket gives an additive inhibitory effect on the YAP:TEAD interaction. Overall, our results show that it is possible to identify nanomolar inhibitors of the YAP:TEAD interaction that bind to the α-helix pocket, suggesting that developing such compounds might be a strategy to treat cancers where the Hippo pathway is deregulated.

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Optimization of a Class of Dihydrobenzofurane Analogs toward Orally Efficacious YAP‐TEAD Protein‐Protein Interaction Inhibitors

et al. 2023

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The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the Ω-loop pocket of TEAD has previously been communicated.This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and offtarget profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time.

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A chemical perspective on the modulation of TEAD transcriptional activities: Recent progress, challenges, and opportunities

Cited by 20 publications

References 166 publications

The Hippo Signaling Pathway as a Drug Target in Familial Dilated Cardiomyopathy

The Hippo Signaling Pathway as a Drug Target in Familial Dilated Cardiomyopathy

Biochemical and Structural Characterization of a Peptidic Inhibitor of the YAP:TEAD Interaction That Binds to the α-Helix Pocket on TEAD

Optimization of a Class of Dihydrobenzofurane Analogs toward Orally Efficacious YAP‐TEAD Protein‐Protein Interaction Inhibitors

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