A5072317400- Cutaneous lymphoproliferative disorders research
- Melanoma and MAPK Pathways
- Synthesis and biological activity
- Lymphoma Diagnosis and Treatment
- X-ray Diffraction in Crystallography
- Heat shock proteins research
- Crystallization and Solubility Studies
- Computational Drug Discovery Methods
- Protein Kinase Regulation and GTPase Signaling
- T-cell and Retrovirus Studies
- Advanced Breast Cancer Therapies
- Chronic Lymphocytic Leukemia Research
- CAR-T cell therapy research
- ATP Synthase and ATPases Research
- Ubiquitin and proteasome pathways
- Protease and Inhibitor Mechanisms
- Cell death mechanisms and regulation
- Enzyme Structure and Function
- Peptidase Inhibition and Analysis
- Genomics, phytochemicals, and oxidative stress
- Synthesis and Biological Evaluation
- Sulfur-Based Synthesis Techniques
- Click Chemistry and Applications
- DNA Repair Mechanisms
- Autoimmune Bullous Skin Diseases
Institute of Medicinal Plant Development
2010
Teddington Memorial Hospital
2009
University of Copenhagen
2004
University of Cambridge
2004
St Thomas' Hospital
1999-2002
St. John's University
2000
University of Surrey
1992
The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led the identification lead series, which retained key interactions initial binding fragments and additionally explored other areas ATP site. majority this paper details structure-guided optimization indazole (6) using information gained from ligand−CDK2 cocrystal...
KEAP1 is the key regulator of NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification cysteine residues, but such electrophilic compounds lack selectivity may be associated with off-target toxicity. We report here first use fragment-based approach to directly Kelch-NRF2 interaction. X-ray crystallographic...
Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and subsequent optimization two hits into leads with inhibitory activities low nanomolar range. This paper describes structure guided 2,4-dihydroxybenzamide lead molecule 1 details some drug discovery...
Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application fragment screening to using a combination NMR and high throughput X-ray crystallography. The identified aminopyrimidine with affinity micromolar range subsequent structure-based design allowed its optimization into low nanomolar series good ligand efficiency. A phenolic chemotype was also found bind close 1 mM. optimized structure based resorcinol lead which has...
The KEAP1–NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signaling during chronic oxidative stress may be associated with the pathophysiology of several diseases an inflammatory component, and pathway activation through direct modulation KEAP1–NRF2 protein–protein interaction is being increasingly explored as potential therapeutic strategy. Nevertheless, physicochemical nature interface suggests that achieving high affinity for...
Inhibitor of apoptosis proteins (IAPs) are important regulators and pro-survival signaling pathways whose deregulation is often associated with tumor genesis growth. IAPs have been proposed as targets for anticancer therapy, a number peptidomimetic IAP antagonists entered clinical trials. Using our fragment-based screening approach, we identified nonpeptidic fragments binding millimolar affinities to both cellular inhibitor protein 1 (cIAP1) X-linked (XIAP). Structure-based hit optimization...
Genetic testing of tumor tissue and circulating cell-free DNA for somatic variants guides patient treatment many cancers. Such measurements will be fundamental in the future support precision medicine. However, there are currently no primary reference measurement procedures available nucleic acid quantification that would translation tests into routine use.We assessed accuracy digital PCR (dPCR) copy number a frequently occurring single-nucleotide variant colorectal cancer (KRAS c.35G>A,...
Background The t(14;18)(q32;q21) chromosomal translocation is found in the majority of nodal follicular lymphomas and a lower percentage systemic high‐grade diffuse large B‐cell lymphomas. results juxtaposition bcl‐2 gene on chromosome 18 with immunoglobulin heavy chain joining region 14. Bcl‐2 protein prevents apoptosis leads to overexpression functionally normal that neoplastic cells. Objectives purpose our study was analyse cases primary cutaneous lymphoma (PCBCL) for presence t(14;18)...
Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors BRAF and MEK kinases are approved for treatment mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe fragment-based generation ERK1/2 inhibitors that block catalytic phosphorylation downstream substrates such as RSK also modulate without directly inhibiting MEK. X-ray crystallographic biophysical fragment screening followed...
Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow design and synthesis of 56 3D disubstituted pyrrolidine piperidine fragments that occupy under-represented areas space (as demonstrated by principal moments inertia (PMI) analysis). A key, unique, underpinning feature this collection assessment shape...
Main text Several scientific fields, such as cytology, biochemistry, molecular biology and genetics have cells their direct topic of study. The cell is a fundamental unit highly technological systems, employed, for example, in the development new chemicals drugs, evaluation compound toxicity, novel approaches to health, regenerative medicine. High content screening technologies are cellular imaging-based assays. In this framework, density, confluency size measurands that can describe...
Childhood cases of cytotoxic T-cell lymphoma have not been well described.We undertaken an immunohistochemical and genotypic analysis patients presenting with juvenile onset mycosis fungoides (MF).Of 10 over a 3-year period, six exhibited CD8-positive phenotype. These were also CD2, CD3 TIA1 positive, but CD56 negative. Apart from the phenotype, these had clinicopathological features that indistinguishable ordinary MF, slowly evolving patches plaques. Three staged as 1A three 1B, no evidence...
The thapsigargins are a family of complex guaianolides with potent and selective Ca 2+ -modulating properties. This article documents the evolution synthetic route through several iterations to final practical scaleable capable generating both unnatural natural products based around guaianolide skeleton.
Nine patients with tumour stage mycosis fungoides (MF) have been entered into a pilot study of T‐cell depletion and autologous stem cell transplantation (SCT). Eight had detectable rearrangements the receptor (TCR) γ‐gene demonstrated by polymerase chain reaction (PCR)/single‐stranded conformation polymorphism (SSCP) in peripheral blood. The median age was 47 years duration disease before SCT 61 months; Peripheral blood progenitor cells were mobilized using high‐dose etoposide (1·6 g/m 2 )...
Herein, we describe the discovery of potent and highly selective inhibitors both CDK4 CDK6 via structure-guided optimization a fragment-based screening hit. X-ray crystallography pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for over CDKs 1 2 an enzymatic assay. Furthermore, 6 demonstrated vivo inhibition pRb-phosphorylation oral efficacy Jeko-1 mouse xenograft model.
The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. protein KEAP1, which regulates NRF2, a key point pharmacological intervention, we recently described the use fragment-based drug discovery develop tool compound that directly disrupts protein-protein interaction between NRF2 KEAP1. We now present identification...
Lymphomatoid papulosis (LyP) is a chronic self-healing cutaneous eruption which clinically benign but histologically malignant. Lesions occur episodically over the trunk and limbs. We describe four patients with regional LyP. All were male, range in age at onset from 12 to 47 years. In all cases, lesions confined segmental unilateral area. Two had type A two B have long-term follow-up on one patient whose limited right buttock for more than 20 years before widespread developed. Another left...
We report two patients with primary cutaneous B-cell lymphoma who were treated rituximab, a new anti-CD20 monoclonal antibody. The first patient, had diffuse large of the lower leg, achieved an 85% improvement. second lymphoma, which undergone high-grade transformation and systemic spread, minor response approximately 30%. Both subsequently relapsed. patient complete clearance course rituximab given chemotherapy, but again Treatment has been reported to produce rates 48% in relapsed...
The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of pathway, ERK an attractive therapeutic target for treatment MAPK-activated cancers and overcoming resistance to upstream inhibition. ASTX029 a highly potent selective dual-mechanism inhibitor, discovered using fragment-based drug design. Because its distinctive ERK-binding mode, inhibits both catalytic activity phosphorylation itself by MEK, despite not directly inhibiting MEK activity....
The importance of DNA as a regulatory analyte is well-known. Recent years have seen an increased interest in the quantitation this analyte. Accurate quantitative measurements been hampered by lack well-characterized standards and pure materials for large-molecular-weight Outlined here approach accurate reproducible oligonucleotide that solely reliant on availability pure, deoxynucleotides not sequence-specific standard. proposed procedure intended to provide definitive method reference...
Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple hits were observed different regions the active site, including some that bound a pocket created by movement protein side chain (approximately 13 Å from catalytic residue Ser273). Using structure guided design, we optimized this generate low nanomolar chemotype, which...