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Pharmaceuticals
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Drug Discovery Targeting the Hippo Signaling Pathway
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Drug Discovery Targeting the Hippo Signaling Pathway

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (28 June 2023) | Viewed by 9835

Special Issue Editors

Dr. Ajaybabu V. Pobbati

E-Mail Website
Guest Editor
1. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
2. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
Interests: hippo pathway; drug discovery; TEAD transcription factors; epithelioid hemangioendothelioma; TAZ-CAMTA1 fusion protein
Special Issues, Collections and Topics in MDPI journals
Dr. Iris Valtingojer

E-Mail Website
Guest Editor
Sanofi Oncology Research Therapeutic Area, 1, impasse des Ateliers, 94400 Vitry-sur-Seine, France
Interests: cancer; hippo-YAP1; resistance to therapy

Special Issue Information

Dear Colleagues,

As the role of the Hippo signaling pathway in cancer and tissue regeneration becomes apparent, small molecules that target the components of this pathway are increasingly being developed and tested for their utility in cancer therapy and regenerative medicine. The druggability of kinases is well established; therefore, two core kinases in this pathway, MST1/2 and LATS1/2, are targeted. Interestingly, the TEAD family of transcription factors has emerged as a novel target. To stimulate oncogenic transcription, TEADs pair with the co-regulators YAP and TAZ. The activity of this transcriptional complex is physiologically inhibited by the Hippo pathway kinases. Small molecule TEAD ligands that inhibit the activity of YAP/TAZ-TEAD have gained considerable traction as anticancer agents. Currently, three TEAD-binding compounds are being tested in clinical trials. Inhibition of LATS/MST kinases, on the other hand, is an avenue to stimulate the activity of the YAP/TAZ-TEAD transcriptional complex, which can be beneficial for improved wound healing and tissue regeneration.

This Special Issue aims to attract manuscripts describing hits and screens, which, when disseminated to the community, result in the development of more favorable pharmaceuticals through collective effort. We are also interested in manuscripts that identify novel druggable targets of the Hippo pathway. Topics that highlight other disease indications where Hippo modulators can be used also fall within the scope of this Special Issue. 

Dr. Ajaybabu V. Pobbati
Dr. Iris Valtingojer
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Hippo pathway
  • YAP
  • TAZ
  • TEAD
  • LATS
  • MST
  • drug discovery
  • high-throughput screens
  • cancer therapy
  • regenerative medicine

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Published Papers (3 papers)

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Research

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16 pages, 5728 KiB  
Article
Comparative Assessment and High-Throughput Drug-Combination Profiling of TEAD-Palmitoylation Inhibitors in Hippo Pathway Deficient Mesothelioma
by Lale Evsen, Patrick J. Morris, Craig J. Thomas and Michele Ceribelli
Pharmaceuticals 2023, 16(12), 1635; https://doi.org/10.3390/ph16121635 - 21 Nov 2023
Cited by 1 | Viewed by 2160
Abstract
The hippo signaling pathway is a central tumor suppressor cascade frequently inactivated in selected human cancers, leading to the aberrant activation of TEAD transcription factors. Whereas several TEAD auto-palmitoylation inhibitors are currently in development, a comprehensive assessment of this novel drug-modality is missing. [...] Read more.
The hippo signaling pathway is a central tumor suppressor cascade frequently inactivated in selected human cancers, leading to the aberrant activation of TEAD transcription factors. Whereas several TEAD auto-palmitoylation inhibitors are currently in development, a comprehensive assessment of this novel drug-modality is missing. Here, we report a comparative analysis among six TEADi(s) using cell-based and biochemical assays in Hippo pathway deficient mesothelioma. Our analysis revealed varying potency and selectivity across TEADi, also highlighting their limited efficacy. To overcome this limitation, we performed an unbiased, quantitative high-throughput drug screening by combining the TEADi VT-103 with a library of approximately 3000 oncology-focused drugs. By exploiting this library’s mechanistic redundancy, we identified several drug-classes robustly synergized with TEADi. These included glucocorticoid-receptor (GR) agonists, Mek1/2 inhibitors, mTOR inhibitors, and PI3K inhibitors, among others. Altogether, we report a coherent single-agent dataset informing on potency and selectivity of TEAD-palmitoylation inhibitors as single-agents. We also describe a rational pipeline enabling the systematic identification of TEAD druggable co-dependencies. This data should support the pre-clinical development of drug combination strategies for the treatment of Hippo-deficient mesothelioma, and more broadly, for other cancers dependent on the oncogenic activity of YAP/TEAD. Full article
(This article belongs to the Special Issue Drug Discovery Targeting the Hippo Signaling Pathway)
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20 pages, 5385 KiB  
Article
TEAD Inhibitors Sensitize KRASG12C Inhibitors via Dual Cell Cycle Arrest in KRASG12C-Mutant NSCLC
by Salvina Laura Tammaccaro, Philippe Prigent, Jean-Christophe Le Bail, Odette Dos-Santos, Laurent Dassencourt, Myriam Eskandar, Armelle Buzy, Olivier Venier, Jean-Claude Guillemot, Yaligara Veeranagouda, Michel Didier, Emmanuel Spanakis, Tokuwa Kanno, Matteo Cesaroni, Stephane Mathieu, Luc Canard, Alhassan Casse, Fanny Windenberger, Loreley Calvet, Laurence Noblet, Sukhvinder Sidhu, Laurent Debussche, Jurgen Moll and Iris Valtingojeradd Show full author list remove Hide full author list
Pharmaceuticals 2023, 16(4), 553; https://doi.org/10.3390/ph16040553 - 6 Apr 2023
Cited by 5 | Viewed by 3381
Abstract
KRASG12C is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRASG12C inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRAS [...] Read more.
KRASG12C is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRASG12C inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRASG12C mutant NSCLC; however, resistance to therapy is emerging. The transcriptional coactivators YAP1/TAZ and the family of transcription factors TEAD1-4 are the downstream effectors of the Hippo pathway and regulate essential cellular processes such as cell proliferation and cell survival. YAP1/TAZ-TEAD activity has further been implicated as a mechanism of resistance to targeted therapies. Here, we investigate the effect of combining TEAD inhibitors with KRASG12C inhibitors in KRASG12C mutant NSCLC tumor models. We show that TEAD inhibitors, while being inactive as single agents in KRASG12C-driven NSCLC cells, enhance KRASG12C inhibitor-mediated anti-tumor efficacy in vitro and in vivo. Mechanistically, the dual inhibition of KRASG12C and TEAD results in the downregulation of MYC and E2F signatures and in the alteration of the G2/M checkpoint, converging in an increase in G1 and a decrease in G2/M cell cycle phases. Our data suggest that the co-inhibition of KRASG12C and TEAD leads to a specific dual cell cycle arrest in KRASG12C NSCLC cells. Full article
(This article belongs to the Special Issue Drug Discovery Targeting the Hippo Signaling Pathway)
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Review

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18 pages, 2328 KiB  
Review
Leveraging Hot Spots of TEAD–Coregulator Interactions in the Design of Direct Small Molecule Protein-Protein Interaction Disruptors Targeting Hippo Pathway Signaling
by Bin Zhao, Ajaybabu V. Pobbati, Brian P. Rubin and Shaun Stauffer
Pharmaceuticals 2023, 16(4), 583; https://doi.org/10.3390/ph16040583 - 13 Apr 2023
Cited by 7 | Viewed by 3153
Abstract
The Hippo signaling pathway is a highly conserved pathway that plays important roles in the regulation of cell proliferation and apoptosis. Transcription factors TEAD1-4 and transcriptional coregulators YAP/TAZ are the downstream effectors of the Hippo pathway and can modulate Hippo biology. Dysregulation of [...] Read more.
The Hippo signaling pathway is a highly conserved pathway that plays important roles in the regulation of cell proliferation and apoptosis. Transcription factors TEAD1-4 and transcriptional coregulators YAP/TAZ are the downstream effectors of the Hippo pathway and can modulate Hippo biology. Dysregulation of this pathway is implicated in tumorigenesis and acquired resistance to therapies. The emerging importance of YAP/TAZ-TEAD interaction in cancer development makes it a potential therapeutic target. In the past decade, disrupting YAP/TAZ-TEAD interaction as an effective approach for cancer treatment has achieved great progress. This approach followed a trajectory wherein peptidomimetic YAP–TEAD protein-protein interaction disruptors (PPIDs) were first designed, followed by the discovery of allosteric small molecule PPIDs, and currently, the development of direct small molecule PPIDs. YAP and TEAD form three interaction interfaces. Interfaces 2 and 3 are amenable for direct PPID design. One direct YAP–TEAD PPID (IAG933) that targets interface 3 has entered a clinical trial in 2021. However, in general, strategically designing effective small molecules PPIDs targeting TEAD interfaces 2 and 3 has been challenging compared with allosteric inhibitor development. This review focuses on the development of direct surface disruptors and discusses the challenges and opportunities for developing potent YAP/TAZ-TEAD inhibitors for the treatment of cancer. Full article
(This article belongs to the Special Issue Drug Discovery Targeting the Hippo Signaling Pathway)
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