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The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.
Pubmed ID: 37277530 RIS Download
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Collection of curated, non-redundant genomic DNA, transcript RNA, and protein sequences produced by NCBI. Provides a reference for genome annotation, gene identification and characterization, mutation and polymorphism analysis, expression studies, and comparative analyses. Accessed through the Nucleotide and Protein databases.
View all literature mentionsA biotechnology corporation that uses human genetic information to discover, develop, manufacture and commercialize medicines to treat patients with serious or life-threatening medical conditions.
View all literature mentionsSoftware to align single and paired end reads as short as 14 nt and of arbitrarily long length. Can detect short and long distance splicing, including interchromosomal splicing, in individual reads, using probabilistic models or database of known splice sites. Permits SNP-tolerant alignment to reference space of all possible combinations of major and minor alleles, and can align reads from bisulfite-treated DNA for study of methylation state.
View all literature mentionsSoftware repository for R packages related to analysis and comprehension of high throughput genomic data. Uses separate set of commands for installation of packages. Software project based on R programming language that provides tools for analysis and comprehension of high throughput genomic data.
View all literature mentionsCommercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.
View all literature mentionsThe Spotfire Gene Ontology Advantage Application integrates GO annotations with gene expression analysis in Spotfire DecisionSite for Functional Genomics. Researchers can select a subset of genes in DecisionSite visualizations and display their distribution in the Gene Ontology hierarchy. Similarly, selection of any process, function or cellular location in the Gene Ontology hierarchy automatically marks the corresponding genes in DecisionSite visualizations. Platform: Windows compatible
View all literature mentionsSoftware tools for Motif Discovery and next-gen sequencing analysis. Used for analyzing ChIP-Seq, GRO-Seq, RNA-Seq, DNase-Seq, Hi-C and numerous other types of functional genomics sequencing data sets. Collection of command line programs for unix style operating systems written in Perl and C++.
View all literature mentionsSoftware package for the analysis of gene expression microarray data, especially the use of linear models for analyzing designed experiments and the assessment of differential expression.
View all literature mentionsSoftware package that includes functions to retrieve the sequences around the peak, obtain enriched Gene Ontology terms, find the nearest gene, exon, miRNA or custom features such as most conserved elements.
View all literature mentionsCompute differentially bound sites from multiple ChIP-seq experiments using affinity (quantitative) data. Also enables occupancy (overlap) analysis and plotting functions.
View all literature mentionsCompany provides laboratories worldwide with analytical instruments and supplies, clinical and diagnostic testing services, consumables, applications and expertise in life sciences and applied chemical markets.
View all literature mentionsSoftware for macromolecular model building, model completion and validation, and protein modelling using X-ray data. Coot displays maps and models and allows model manipulations such as idealization, rigid-body fitting, ligand search, Ramachandran plots, non-crystallographic symmetry and more. Source code is available.
View all literature mentionsSoftware package for NMR spectra acquisition, processing, and data analysis. Features include: deconvolution/spectrum simulation/iteration; comprehensive functionalities for processing, displaying and analyzing one and multi-dimensional spectra; and user customization. A full list of features is available on the website.
View all literature mentionsSoftware package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.
View all literature mentionsCell line MDA-MB-231 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionslaboratory mouse with name C57BL/6 from MGI.
View all literature mentionsCell line NCI-H226 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H358 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H23 is a Cancer cell line with a species of origin Homo sapiens (Human)
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