Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction

Bum‐Erdene, Khuchtumur; Zhou, Dongfang; González-Gutiérrez, Giovanni; Ghozayel, Mona K.; Si, Yubing; Xu, David; Shannon, Harlan E.; Bailey, Barbara J.; Corson, Timothy W.; Pollok, Karen E.; Wells, Clark D.; Meroueh, Samy O.

doi:10.1016/j.chembiol.2018.11.010

Cited by 135 publications

(118 citation statements)

References 63 publications

(71 reference statements)

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“…Another YAP inhibitor, CA3, has been reported to modulate the YAP/TEAD transcriptional activity and decrease YAP expression [111]. Studies with Flufenamic acid has shown reduced cell growth, TEAD reporter activity and various Hippo pathway responsive genes [112]. These studies suggest that disruption of downstream transcription complexes could be a promising therapeutic approach.…”

Section: Hippo Signaling Pathwaymentioning

confidence: 94%

Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma

Dimri

Satyanarayana

2020

Cancers

216

168

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Hepatocellular carcinoma (HCC) is a complex biological process and is often diagnosed at advanced stages with no effective treatment options. With advances in tumor biology and molecular genetic profiling, several different signaling pathways and molecular mechanisms have been identified as responsible for initiating and promoting HCC. Targeting these critical pathways, which include the receptor tyrosine kinase pathways, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK), the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), the Wnt/β-catenin signaling pathway, the ubiquitin/proteasome degradation and the hedgehog signaling pathway has led to the identification of novel therapeutics for HCC treatment. In this review, we elaborated on our current understanding of the signaling pathways involved in the development and initiation of HCC and anticipate the potential targets for therapeutic drug development.

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Section: Hippo Signaling Pathwaymentioning

confidence: 94%

Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma

Dimri

Satyanarayana

2020

Cancers

216

168

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“…However, the underlying mechanism remains unclear. More recently, an independent group identified flufenamic acid derivatives (Table 1, compound 7) comprising chloromethyl ketone moieties that bind to the conserved cysteine in the lipid pocket, thus inhibiting YAP-TEAD interaction, transcriptional activity, and glioblastoma growth in vitro [61].…”

Section: Targeting the Hippo Pathway In Cancermentioning

confidence: 99%

Hippo Pathway in Cancer: Aberrant Regulation and Therapeutic Opportunities

Calses¹,

Crawford²,

Lill³

et al. 2019

Trends in Cancer

284

220

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The Hippo pathway remains a central focus in both basic and translational research and is a key modulator of developmental biology. Dysregulation of the pathway is associated with a plethora of human cancers and there are multiple efforts to target key components of the pathway for disease intervention. In this review, we briefly highlight the latest research advances around the core components of the Hippo pathway in cancer. More specifically, we discuss several genetic aberrations of these factors as mechanisms for the development of cancers, including genetic amplification, deletion, and gene fusions. Additionally, we highlight the role of the Hippo pathway in cancer therapy resistance and tumor immunogenicity. Last, we summarize the ongoing efforts to target the pathway in cancers. The Hippo Pathway The Hippo pathway is a highly conserved signaling pathway across higher-order vertebrates that modulates key target genes to regulate a multitude of biological processes including cellular proliferation, survival, differentiation, cellular fate determination, organ size, and tissue homeostasis (Figure 1). At the core of the pathway are serine/threonine kinases, sterile 20-like kinase 1/2 (MST1/2), and large tumor suppressor 1/2 (LATS1/2). Recently, MAP4K and TAOK kinases have been shown to directly phosphorylate LATS1/2, thus acting in parallel with MST1/2 [1]. These kinases, along with the adaptor proteins, Salvador homolog 1 (SAV1) and MOB kinase activator 1A/B (MOB1A/B), phosphorylate and inhibit downstream effector proteins, Yesassociated protein (YAP1), and its paralog transcriptional coactivator with PDZ-binding motif (TAZ) (also known as WWTR1) and sequestrates them in the cytoplasm by binding to 14-3-3 proteins [2]. Notably, the tumor suppressor neurofibromin 2 (NF2) (also known as Merlin) participates upstream of these kinases to inhibit YAP and TAZ activity by promoting the activation of the pathway. Additional phosphorylation of YAP/TAZ leads to proteasome-mediated degradation facilitated by binding to β-TrCP [3,4]. Such regulation prevents YAP/TAZ from accumulating in the nucleus and from binding to a family of sequence-specific transcription factors called TEA DNA-binding proteins (TEAD1-4) that mediate proliferative and prosurvival genes such as CTGF, CRY61, BIRC5, ANKRD1, and AXL (Figure 2). Besides TEADs, YAP/TAZ also cooperates with RUNT-related transcription factors (RUNX1 and 2), T-box transcription factor 5 (TBX5), and SMADs as among others [2,5]. Hippo Pathway Deregulation in Cancer Overexpression of Hippo Pathway Effector Proteins Aberration of the Hippo pathway is associated with the hallmarks of oncogenesis and, more recently, has been linked to other cellular processes such as regulation of T cell functionality [6]. These hallmarks include the induction of hyperproliferation, cellular invasion, and metastasis, as well as a role in cancer cell maintenance and chemotherapeutic resistance mechanisms. Analysis of over 9000 tumors showed that YAP and TAZ are frequently amplified in head and nec...

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“…Using fragment-based and computational modeling approaches, the Ω-loop or the α-helix protein interaction domain on YAP, and a hydrophobic palmitoylation pocket on TEAD were identified as targetable domains [233,234,237]. Peptides binding to this pocket may serve as scaffolds for the development of compounds with the potential to break the YAP/TAZ-TEAD interaction [238], and several such compounds are currently in pharmaceutical development [239][240][241][242] (Figure 4). Cells 2020, 9, x 19 of 33 YAP and TAZ are often activated as an alternative survival pathway in drug-resistant cells and can be involved in mechanisms inducing drug resistance [27].…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Kovar

Bierbaumer

Radic-Sarikas

2020

Cells

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YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer.Cells 2020, 9, 972 2 of 34 co-activators Yes-associated protein 1 (YAP-1, YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ, WWTR1), which are typically controlled on the post-translational level by upstream regulatory signaling pathways in organ development and tissue homeostasis [2,3]. YAP and TAZ were reported to affect self-renewal and lineage commitment of stem cells [4][5][6][7], while hyperactivation of YAP and TAZ have been linked to cancer growth and metastasis in various tumors [8][9][10]. TAZ levels are elevated in approximately 20% of cancers and drive invasion and metastasis [11,12], while YAP is frequently overexpressed or amplified in cancer and was shown to promote resistance to chemotherapy in oncogene-addicted tumors up...

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Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction

Cited by 135 publications

References 63 publications

Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma

Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma

Hippo Pathway in Cancer: Aberrant Regulation and Therapeutic Opportunities

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

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