A5034979188- Cancer-related Molecular Pathways
- Advanced Breast Cancer Therapies
- Genomics and Rare Diseases
- Genetic Associations and Epidemiology
- Cancer Mechanisms and Therapy
- Forensic and Genetic Research
- Click Chemistry and Applications
- CRISPR and Genetic Engineering
- Radiomics and Machine Learning in Medical Imaging
- Genomic variations and chromosomal abnormalities
- Cancer therapeutics and mechanisms
- Biotechnology and Related Fields
- Cytokine Signaling Pathways and Interactions
- Axon Guidance and Neuronal Signaling
- Ubiquitin and proteasome pathways
- Genetics, Bioinformatics, and Biomedical Research
- Cancer Research and Treatments
- Protein Degradation and Inhibitors
- Protease and Inhibitor Mechanisms
- Microtubule and mitosis dynamics
- Chronic Lymphocytic Leukemia Research
- Advanced Proteomics Techniques and Applications
- Cancer-related gene regulation
- Genetics and Neurodevelopmental Disorders
- Wnt/β-catenin signaling in development and cancer
Zero to Three
2023
Cancer Research UK
2015-2019
Institute of Cancer Research
2015-2019
The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly colorectal cancer where it reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), potent, selective, and orally bioavailable inhibitor with equipotent affinity for CDK19. We describe structure-based design approach leading to 3,4,5-trisubstituted-2-aminopyridine series present application physicochemical property analyses successfully reduce vivo...
Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it unclear whether this will impact on the clinical utility inhibitors. We discovered two series potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence robust on-target activity, compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts....
WNT signaling is frequently deregulated in malignancy, particularly colon cancer, and plays a key role the generation maintenance of cancer stem cells. We report discovery optimization 3,4,5-trisubstituted pyridine 9 using high-throughput cell-based reporter assay pathway activity. demonstrate twisted conformation about pyridine–piperidine bond by small-molecule X-ray crystallography. Medicinal chemistry to maintain this conformation, cognisant physicochemical properties likely good cell...
The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. activity regulated by the reversible association a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 MED12L, and MED13 MED13L. Mutations in MED12, MED13, MED13L were previously identified syndromic developmental disorders overlapping phenotypes. Here, we report mutations (located at 13q12.13) cause phenotypically related disorder. Using...
African populations have been drastically underrepresented in genomics research, and failure to capture the genetic diversity across numerous ethnolinguistic groups (ELGs) found on continent has hindered equity of precision medicine initiatives globally. Here, we describe whole-genome sequencing 449 Nigerian individuals 47 unique self-reported ELGs. Population structure analysis reveals differentiation among our ELGs, consistent with previous findings. From 36 million SNPs insertions or...
Abstract Background CDK8 and CDK19 are two highly homologous cyclin-dependent kinases involved in gene transcription via the Mediator complex. Individual kinase module paralogs (CDK8 or CDK19) complex with cyclin C, Med13 Med12 regulate through phosphorylation of C-terminal domain RNAPol II. Despite their structural similarities, emerging data suggest possible distinct transcriptional regulatory functions. There few studies function, but has been described as an oncogene CRC, required for...
Abstract Background The Mediator complex-associated kinases CDK8 and CDK19 are cyclin C-dependent enzymes that, with MED12 MED13, form the kinase module of complex. expression correlates activation β-catenin in colon gastric cancers has also been associated increased mortality colorectal, breast ovarian cancers. is located a region chromosome 13 known to undergo copy number gain ∼60% colorectal inducible shRNA-mediated knockdown protein reduces growth cancer human tumor xenograft animal...
Summary African populations have been drastically underrepresented in genomics research and failure to capture the genetic diversity across numerous ethnolinguistic groups (ELGs) found continent has hindered equity of precision medicine initiatives globally. Here, we describe whole-genome sequencing 449 Nigerian individuals 47 unique self-reported ELGs. Population structure analysis reveals differentiation amongst our ELGs, consistent with previous findings. From 36 million SNPs INDELs...
Abstract The discovery of chemical probes by testing libraries small molecules against cellular pathway screens has re-emerged as a hit strategy. We previously reported series 3,4,5-trisubstituted pyridines identified from high-throughput cell-based reporter assay WNT signalling. were able to optimise this and CCT251545 tool that potently inhibits readouts signalling activity with evidence for in vivo activity. A assays activating at distinct loci the TCF locale likely target. was not...
Abstract Introduction CDK8 is an oncogenic cyclin-dependent kinase that exists as part of the module within Mediator complex. This complex interacts with transcription machinery to regulate transcription; signal transduction pathways, including WNT pathway; and biological processes, such cell cycle progression. Recently, we identified a series 3,4,5-trisubstituted pyridines inhibitors and, its paralogue, CDK19 in colorectal cancer (CRC). Until now, there have been few validated substrates...
Abstract Mediator-associated protein kinases CDK8 and CDK19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it unclear whether this will impact on the clinical utility CDK8/19 inhibitors. We identified two structurally differentiated chemical series, suitable for exploring their function. In addition tools that fulfil criteria set out probes, lead compounds from each CCT251921 MSC2530818, had optimal...
Abstract Introduction: CDK8 and its paralogue CDK19 are highly similar cyclin-dependent kinases that function as components of the kinase module Mediator complex. Despite their structural similarity, emerging data suggest these proteins may have distinct functions in regulation transcription. Recently, we identified two chemical series CDK8/19 ligands (1, 2); however, binding affinities for it has not been possible, until now, to determine if biologic effects observed were driven by...
ABSTRACT Proteomic variation between individuals has immense potential for identifying novel drug targets and disease mechanisms. However, with high-throughput proteomic technologies still in their infancy, they have largely been applied large majority European ancestry cohorts (e.g. the UK Biobank). An open question is degree to which signatures seen other groups mirror those diverse populations, such as from Africa. Coupled genetic information, we can also gain a better understanding of...