Searching across hundreds of databases
Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors.
Pubmed ID: 27935476 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.
View all literature mentionsFunctional genomics data repository supporting MIAME-compliant data submissions. Includes microarray-based experiments measuring the abundance of mRNA, genomic DNA, and protein molecules, as well as non-array-based technologies such as serial analysis of gene expression (SAGE) and mass spectrometry proteomic technology. Array- and sequence-based data are accepted. Collection of curated gene expression DataSets, as well as original Series and Platform records. The database can be searched using keywords, organism, DataSet type and authors. DataSet records contain additional resources including cluster tools and differential expression queries.
View all literature mentionsFunctional genomics data repository supporting MIAME-compliant data submissions. Includes microarray-based experiments measuring the abundance of mRNA, genomic DNA, and protein molecules, as well as non-array-based technologies such as serial analysis of gene expression (SAGE) and mass spectrometry proteomic technology. Array- and sequence-based data are accepted. Collection of curated gene expression DataSets, as well as original Series and Platform records. The database can be searched using keywords, organism, DataSet type and authors. DataSet records contain additional resources including cluster tools and differential expression queries.
View all literature mentionsCell line Caco-2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis monoclonal targets beta-Actin
View all literature mentionsThis polyclonal targets STAT1
View all literature mentionsThis polyclonal targets CDK19
View all literature mentionsThis polyclonal targets CDK8
View all literature mentionsCell line DLD-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSoftware package for interpreting gene expression data. Used for interpretation of a large-scale experiment by identifying pathways and processes.
View all literature mentionsCell line SW837 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line LS180 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line RKO is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE. Documented on March 17, 2022. An integrated software suite for functional analysis of experimental data. The scope of data types includes microarray and SAGE gene expression, SNPs and CGH arrays, proteomics, metabolomics, pathway analysis, Y2H and other custom interactions. MetaCore is based on a proprietary manually curated database of human protein-protein, protein-DNA and protein compound interactions, metabolic and signaling pathways and the effects of bioactive molecules in gene expression.
View all literature mentionsA desktop analysis workbench for analyzing high-volume, high-density genotyping data. The software provides a comprehensive set of linkage and association algorithms that allow researchers to discover relationships between genotypes and phenotypes. Researchers can visually explore fully annotated SNPs and genes at varying levels of detail. Designed for biologists and statisticians, GeneSpring GT is capable of importing, visualizing, and analyzing hundreds of thousands of variation measurements simultaneously, for rapid localization of disease or phenotype markers. (entry from Genetic Analysis Software)
View all literature mentionsCell line SW948 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line LS513 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line SW620 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line LS174T is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HT-29 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line COLO 205 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThe SciCrunch Infrastructure was developed as a cooperative data platform to be used by diverse communities in making data more FAIR.
scicrunch.org
