A5016800025- Peptidase Inhibition and Analysis
- Cancer Research and Treatments
- Neuroendocrine Tumor Research Advances
- Adenosine and Purinergic Signaling
- Cell Adhesion Molecules Research
- Cancer-related Molecular Pathways
- Protease and Inhibitor Mechanisms
- Hippo pathway signaling and YAP/TAZ
- Advanced Breast Cancer Therapies
- Ubiquitin and proteasome pathways
- Wnt/β-catenin signaling in development and cancer
- Cellular Mechanics and Interactions
- Cellular transport and secretion
- Cancer Genomics and Diagnostics
- S100 Proteins and Annexins
- Signaling Pathways in Disease
- Cancer Mechanisms and Therapy
- Blood Coagulation and Thrombosis Mechanisms
- Chronic Lymphocytic Leukemia Research
- Cancer Cells and Metastasis
- Nanoplatforms for cancer theranostics
- Cancer therapeutics and mechanisms
- Glycosylation and Glycoproteins Research
- Caveolin-1 and cellular processes
- Cancer-related gene regulation
Merck (Germany)
2015-2024
Breast Cancer Now
2006-2023
Institute of Cancer Research
2002-2023
University of British Columbia
2006
MRC Laboratory for Molecular Cell Biology
2006
University College London
2006
Breast Cancer Research Foundation
2003-2005
Agrobioinstitute
1999
Darmstadt University of Applied Sciences
1996
Abstract Colorectal carcinoma represents a heterogeneous entity, with only fraction of the tumours responding to available therapies, requiring better molecular understanding disease in precision oncology. To address this challenge, OncoTrack consortium recruited 106 CRC patients (stages I–IV) and developed pre-clinical platform generating compendium drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived vivo vitro models. This large biobank tumours, 35...
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...
The mediator complex-associated cyclin dependent kinase CDK8 regulates β-catenin-dependent transcription following activation of WNT signaling. Multiple lines evidence suggest may act as an oncogene in the development colorectal cancer. Here we describe successful optimization imidazo-thiadiazole series inhibitors that was identified a high-throughput screening campaign and further progressed by structure-based design. In several cycles, improved microsomal stability, potency, selectivity....
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....
Fibroblasts are a diverse cell type and display clear topographic differentiation positional memory. In screen for fibroblast specific markers we have characterized four monoclonal antibodies to endosialin (TEM1/CD248). Previous studies reported that is tumour endothelium marker localized intracellularly. We demonstrate conclusively surface glycoprotein predominantly expressed by fibroblasts subset of pericytes associated with vessels but not endothelium. These novel will facilitate the...
Abstract Mannose receptor (MR) is the best characterised member of a family four endocytic molecules that share common domain structure; cysteine‐rich (CR) domain, fibronectin‐type II (FNII) and tandemly arranged C‐type lectin‐like domains (CTLD, eight in case MR). Two distinct lectin activities have been described for MR. The CR recognises sulphated carbohydrates while CTLD mediate binding to mannose, fucose or N ‐acetylglucosamine. FNII are known be important collagen this has studied...
Endo180, a member of the mannose receptor family, is constitutively recycled between clathrin-coated pits on cell surface and intracellular endosomes. Its large extracellular domain contains an N-terminal cysteine-rich domain, single fibronectin type II eight C-type lectin-like domains. The second these domains has been shown to mediate Ca2+-dependent binding. In addition, cross-linking studies have identified Endo180 as urokinase plasminogen activator receptor-associated protein this...
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 dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention triggered gene transcription an attractive strategy for therapeutic intervention. deeply buried and conserved lipidation pocket (P-site) TEAD factors druggable. discovery optimization a P-site binding fragment (1) are described. Utilizing structure-based design, enhancement in target potency was engineered into hit, capitalizing...
The identification and functional characterization ofDictyostelium discoideum dynamin A, a protein composed of 853 amino acids that shares up to 44% sequence identity with other dynamin-related proteins, is described. Dynamin A present during all stages D. development found predominantly in the cytosolic fraction association endosomal postlysosomal vacuoles. Overexpression has no adverse effect on cells, whereas depletion by gene-targeting techniques leads multiple complex phenotypic...
The mannose receptor family comprises four members in mammals, Endo180 (CD280), DEC-205 (CD205), phospholipase A(2) (PLA(2)R) and the (MR, CD206), whose extracellular portion contains a similar domain arrangement: an N-terminal cysteine-rich (CysR) followed by single fibronectin type II (FNII) 8-10 C-type lectin-like domains (CTLDs). These proteins mediate diverse functions ranging from matrix turnover through collagen uptake to homeostasis immunity based on sugar recognition. MR are...
Abstract Tumor cell invasion into the surrounding stroma requires increased motility and extensive remodeling of extracellular matrix. Endo180 (CD280, MRC2, urokinase-type plasminogen activator receptor-associated protein) is a recycling endocytic receptor that functions in both these cellular activities by promoting migration uptake collagens for intracellular degradation. In normal breast, predominantly expressed stromal fibroblasts. The contrary observation on epithelial tumor lines...
Abstract Inhibition of the PARP superfamily tankyrase enzymes suppresses Wnt/β-catenin signalling in tumour cells. Here, we describe here a novel, drug-like small molecule inhibitor MSC2504877 that inhibits growth APC mutant colorectal Parallel siRNA and drug sensitivity screens showed clinical CDK4/6 palbociclib, causes enhanced to MSC2504877. This inhibitor-CDK4/6 combinatorial effect is not limited palbociclib elicited with other inhibitors toolbox inhibitors. The addition enhances G 1...
The regulated assembly and disassembly of focal adhesions adherens junctions contributes to cell motility tumor invasion. Pivotal in this process is phosphorylation myosin light chain-2 (MLC2) by Rho kinase (ROCK) downstream activation, which generates the contractile force necessary drive epithelial cell–cell cell–matrix at rear migrating cells. How Rho–ROCK–MLC2 activation occurs these distinct cellular locations not known, but emerging concept that endocytic dynamics can coordinate key...
We demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid aldehyde oxidase-mediated metabolism, which could be abrogated by introduction an amino substituent at C5 1,6-naphthyridine scaffold or C1 isoquinoline scaffold. Compounds 51 59 were progressed vivo pharmacokinetic studies, also demonstrated sustained inhibition STAT1(SER727)...
Abstract Background Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools measure the level of in subtypes response systemic therapy are largely lacking. A transcriptomic signature would be warranted, for example monitor effects future Notch-targeting therapies learn whether altered is an off-target effect current therapies. In this report, we have established such a classifier. Methods To generate signature, first identified...
Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in cell guidance chemotaxis during normal pathological events. uPAR is GPI-anchored the mechanism by which it transmits intracellular polarity cues across plasma membrane directional sensing has not been elucidated. The constitutively recycling endocytic Endo180 forms a trimolecular complex with presence of uPA, hence alternate name uPAR-associated protein. Here, we demonstrate that general promoter...
Induction of cytochrome P450 (CYP) genes constitutes an important cause drug-drug interactions and preclinical evaluation induction liability is mandatory for novel drug candidates. YAP/TEAD signaling has emerged as attractive target various oncological indications multiple chemically distinct inhibitors are rapidly progressing towards clinical stages. Here, we tested the CYP a diverse set with different modes action TEAD isoform selectivity profiles in monolayers 3D spheroids primary human...
Type I collagen is a fibril-forming heterotrimer composed of two α1 and one α2 chains plays crucial role in cell-matrix adhesion cell differentiation. Through comprehensive differential display screening oncogenic ras target genes, we have shown that the chain type (col1a1) markedly down-regulated by oncogene through mitogen-activated protein kinase pathway. Although ras-transformed cells are no longer able to produce secrete endogenous collagen, they can still adhere exogenous suggesting...
Aberrant activation of the Wnt signalling pathway is required for tumour initiation and survival in majority colorectal cancers. The development inhibitors has been focus multiple drug discovery programs targeting cancer other malignancies associated with aberrant activation. However, progression new clinical entities slow. One challenge lies limited predictive power 2D cell lines because they fail to fully recapitulate intratumoural phenotypic heterogeneity. In particular, relationship...
Aims: Interactions of cells with the extracellular matrix are important for normal wound healing and may play a role in scar formation. Remarkably, human gingiva does not result formation serves as model regeneration. Endo180 (CD280) is cell surface receptor that has novel functions to regulate migration bind internalize collagens key processes healing. The aim this study was examine expression during gingival Methods results: Biopsies were collected from 1–60 days after wounding analysed by...