The Hippo Pathway as Drug Targets in Cancer Therapy and Regenerative Medicine

2017 ◽  
Vol 18 (4) ◽  
pp. 447-454 ◽  
Author(s):  
Shunta Nagashima ◽  
Yijun Bao ◽  
Yutaka Hata
Keyword(s):  
Cancer Therapy ◽  
Regenerative Medicine ◽  
Drug Targets ◽  
Hippo Pathway ◽  
The Hippo Pathway

scholarly journals Targeting the Hippo Pathway for Breast Cancer Therapy

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 422 ◽  
Author(s):  
Liqing Wu ◽  
Xiaolong Yang
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Targeted Therapies ◽  
Hippo Pathway ◽  
Targeted Drugs ◽  
Breast Cancer Therapy ◽  
The World ◽  
Core Components ◽  
Future Direction ◽  
The Hippo Pathway

Breast cancer (BC) is one of the most prominent diseases in the world, and the treatments for BC have many limitations, such as resistance and a lack of reliable biomarkers. Currently the Hippo pathway is emerging as a tumor suppressor pathway with its four core components that regulate downstream transcriptional targets. In this review, we introduce the present targeted therapies of BC, and then discuss the roles of the Hippo pathway in BC. Finally, we summarize the evidence of the small molecule inhibitors that target the Hippo pathway, and then discuss the possibilities and future direction of the Hippo-targeted drugs for BC therapy.

scholarly journals Reciprocal Regulation of Hippo and WBP2 Signalling—Implications in Cancer Therapy

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3130
Author(s):  
Yvonne Xinyi Lim ◽  
Hexian Lin ◽  
Sock Hong Seah ◽  
Yoon Pin Lim
Keyword(s):  
Cancer Therapy ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Biological Mechanisms ◽  
Reciprocal Regulation ◽  
Cancer Initiation ◽  
The Hippo Pathway ◽  
Global Health Problem ◽  
Hippo Signalling

Cancer is a global health problem. The delineation of molecular mechanisms pertinent to cancer initiation and development has spurred cancer therapy in the form of precision medicine. The Hippo signalling pathway is a tumour suppressor pathway implicated in a multitude of cancers. Elucidation of the Hippo pathway has revealed an increasing number of regulators that are implicated, some being potential therapeutic targets for cancer interventions. WW domain-binding protein 2 (WBP2) is an oncogenic transcriptional co-factor that interacts, amongst others, with two other transcriptional co-activators, YAP and TAZ, in the Hippo pathway. WBP2 was recently discovered to modulate the upstream Hippo signalling components by associating with LATS2 and WWC3. Exacerbating the complexity of the WBP2/Hippo network, WBP2 itself is reciprocally regulated by Hippo-mediated microRNA biogenesis, contributing to a positive feedback loop that further drives carcinogenesis. Here, we summarise the biological mechanisms of WBP2/Hippo reciprocal regulation and propose therapeutic strategies to overcome Hippo defects in cancers through targeting WBP2.

The Hippo Pathway and YAP/TAZ–TEAD Protein–Protein Interaction as Targets for Regenerative Medicine and Cancer Treatment

2015 ◽  
Vol 58 (12) ◽  
pp. 4857-4873 ◽  
Author(s):  
Matteo Santucci ◽  
Tatiana Vignudelli ◽  
Stefania Ferrari ◽  
Marco Mor ◽  
Laura Scalvini ◽  
...  
Keyword(s):  
Regenerative Medicine ◽  
Cancer Treatment ◽  
Protein Interaction ◽  
Hippo Pathway ◽  
Protein Protein Interaction ◽  
The Hippo Pathway

scholarly journals Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine

2020 ◽  
Vol 19 (7) ◽  
pp. 480-494 ◽  
Author(s):  
Anwesha Dey ◽  
Xaralabos Varelas ◽  
Kun-Liang Guan
Keyword(s):  
Wound Healing ◽  
Regenerative Medicine ◽  
Hippo Pathway ◽  
The Hippo Pathway

scholarly journals Recent Therapeutic Approaches to Modulate the Hippo Pathway in Oncology and Regenerative Medicine

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2715
Author(s):  
Evan R. Barry ◽  
Vladimir Simov ◽  
Iris Valtingojer ◽  
Olivier Venier
Keyword(s):  
Regenerative Medicine ◽  
Small Molecules ◽  
Hippo Pathway ◽  
Therapeutic Approaches ◽  
Tumor Immune Evasion ◽  
Multiple Modalities ◽  
Protein Protein Interaction ◽  
Cancer Settings ◽  
The Hippo Pathway ◽  
Resistance To Chemotherapy

The Hippo pathway is an evolutionary conserved signaling network that regulates essential processes such as organ size, cell proliferation, migration, stemness and apoptosis. Alterations in this pathway are commonly found in solid tumors and can lead to hyperproliferation, resistance to chemotherapy, compensation for mKRAS and tumor immune evasion. As the terminal effectors of the Hippo pathway, the transcriptional coactivators YAP1/TAZ and the transcription factors TEAD1–4 present exciting opportunities to pharmacologically modulate the Hippo biology in cancer settings, inflammation and regenerative medicine. This review will provide an overview of the progress and current strategies to directly and indirectly target the YAP1/TAZ protein–protein interaction (PPI) with TEAD1–4 across multiple modalities, with focus on recent small molecules able to selectively bind to TEAD, block its autopalmitoylation and inhibit YAP1/TAZ–TEAD-dependent transcription in cancer.

scholarly journals Identification of Celastrol as a Novel YAP-TEAD Inhibitor for Cancer Therapy by High Throughput Screening with Ultrasensitive YAP/TAZ–TEAD Biosensors

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1596 ◽  
Author(s):  
Kazem Nouri ◽  
Taha Azad ◽  
Min Ling ◽  
Helena J. Janse van Rensburg ◽  
Alexander Pipchuk ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Hippo Pathway ◽  
Cancer Cell Proliferation ◽  
Protein Protein Interaction ◽  
The Hippo Pathway ◽  
Future Work

The Hippo pathway has emerged as a key signaling pathway that regulates a broad range of biological functions, and dysregulation of the Hippo pathway is a feature of a variety of cancers. Given this, some have suggested that disrupting the interaction of the Hippo core component YAP and its paralog TAZ with transcriptional factor TEAD may be an effective strategy for cancer therapy. However, there are currently no clinically available drugs targeting the YAP/TAZ–TEAD interaction for cancer treatment. To facilitate screens for small molecule compounds that disrupt the YAP–TEAD interaction, we have developed the first ultra-bright NanoLuc biosensor to quantify YAP/TAZ–TEAD protein–protein interaction (PPI) both in living cells and also in vitro using biosensor fusion proteins purified from bacteria. Using this biosensor, we have performed an in vitro high throughput screen (HTS) of small molecule compounds and have identified and validated the drug Celastrol as a novel inhibitor of YAP/TAZ–TEAD interaction. We have also demonstrated that Celastrol can inhibit cancer cell proliferation, transformation, and cell migration. In this study, we describe a new inhibitor of the YAP/TAZ–TEAD interaction warranting further investigation and offer a novel biosensor tool for the discovery of other new Hippo-targeting drugs in future work.

Discovery of an Unexpected Similarity in Ligand Binding Between BRD4 and PPARγ

2019 ◽  
Author(s):  
Lina Humbeck ◽  
Jette Pretzel ◽  
Saskia Spitzer ◽  
Oliver Koch
Keyword(s):  
Cancer Therapy ◽  
Drug Targets ◽  
Synergistic Effects ◽  
Complex Structure ◽  
Peroxisome Proliferator ◽  
Resistance Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Starting Point ◽  
Fundamental Research ◽  
Important Drug

Knowledge about interrelationships between different proteins is crucial in fundamental research for the elucidation of protein networks and pathways. Furthermore, it is especially critical in chemical biology to identify further key regulators of a disease and to take advantage of polypharmacology effects. A comprehensive scaffold-based analysis uncovered an unexpected relationship between bromodomain-containing protein 4 (BRD4) and peroxisome-proliferator activated receptor gamma (PPARγ). They are both important drug targets for cancer therapy and many more important diseases. Both proteins share binding site similarities near a common hydrophobic subpocket which should allow the design of a polypharmacology-based ligand targeting both proteins. Such a dual-BRD4-PPARγ-modulator could show synergistic effects with a higher efficacy or delayed resistance development in, for example, cancer therapy. Thereon, a complex structure of sulfasalazine was obtained that involves two bromodomains and could be a potential starting point for the design of a bivalent BRD4 inhibitor.

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