A5014888015- Computational Drug Discovery Methods
- Heat shock proteins research
- Monoclonal and Polyclonal Antibodies Research
- Click Chemistry and Applications
- PI3K/AKT/mTOR signaling in cancer
- Protein Degradation and Inhibitors
- Enzyme Structure and Function
- Cancer-related Molecular Pathways
- Chemical Synthesis and Analysis
- ATP Synthase and ATPases Research
- Biochemical and Molecular Research
- Hepatitis C virus research
- Cancer therapeutics and mechanisms
- thermodynamics and calorimetric analyses
- Melanoma and MAPK Pathways
- X-ray Diffraction in Crystallography
- Endoplasmic Reticulum Stress and Disease
- Crystallization and Solubility Studies
- Tuberculosis Research and Epidemiology
- Advanced Breast Cancer Therapies
- Mental Health and Patient Involvement
- Systemic Lupus Erythematosus Research
- Cytokine Signaling Pathways and Interactions
- Lysosomal Storage Disorders Research
- Interprofessional Education and Collaboration
Dementia UK
2024
Wellington Hospital
2019
University of Oslo
2012
Oxford University Press (United Kingdom)
1969
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...
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...
We describe the structure-guided optimization of molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 35 microM) identified using X-ray crystallographic screening p38alpha MAP kinase. Using two separate case studies, article focuses on key compounds synthesized, structure-activity relationships binding mode observations made during this process, resulting in potent lead series that demonstrate significant increases activity. process compound...
The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown pharmacological inhibition suppresses RAS/MAPK inhibit the proliferation RTK-driven cancer cell lines. Here, we describe first reported fragment-to-lead campaign against SHP2, where X-ray crystallography biophysical techniques were used to identify fragments binding multiple sites on SHP2....
Abstract Background: ASTX295 is a potent MDM2 antagonist designed to have shorter half-life (t1/2 4-6 hours in plasma), which leads an improved safety profile (bone-marrow sparing), making it more amenable combinations compared other antagonists. The recent success of targeting TP53:Y220C mutant cancers with p53 corrector molecule holds great promise for treatment all Y220C TP53 cancers. However, effective therapy, high level signalling will be required overcome the elevated apoptotic...
β-Glucocerebrosidase (GBA/GCase) mutations leading to misfolded protein cause Gaucher's disease and are a major genetic risk factor for Parkinson's dementia with Lewy bodies. The identification of small molecule pharmacological chaperones that can stabilize the increase delivery degradation-prone mutant GCase lysosome is strategy under active investigation. Here, we describe first use fragment-based drug discovery (FBDD) identify GCase. fragment hits were identified by using X-ray...
Abstract Eukaryotic initiation factor 4E (eIF4E) serves as a regulatory hub for oncogene-driven protein synthesis and is considered promising anticancer target. Here we screen fragment library against eIF4E identify ligand-binding site with previously unknown function. Follow-up structure-based design yields low nM tool compound ( 4 , K d = 0.09 µM; LE 0.38), which disrupts the eIF4E:eIF4G interaction, inhibits translation in cell lysates, demonstrates target engagement intact cells (EC 50 2...
Abstract The translation initiation factor eIF4E is a rate-limiting for protein synthesis that binds the mRNA m7G-cap to initiate recruitment and binding of eIF4F components such as eIF4G. Targeting has long been considered promising anticancer strategy but it remained undruggable using conventional screening approaches. Fragment-based crystallographic powerful technique probing surface proteins identify potentially druggable sites. Here, we describe fragment-based combination Xray...
Abstract MAPK pathway activation is a feature of multiple tumor types. Drugging KRAS and BRAF, the two main oncogenic drivers in pathway, has proven successful clinic. Inhibition downstream effectors, MEK ERK, can also induce regression. Despite this, many tumors are intrinsically resistant to inhibitors, or acquire resistance under selective pressure drug treatment. This creates need for combination treatments improve clinical responses. A synthetic lethal (SL) interaction between...
In line with increasing participatory approaches to service and research design, there is a growing appreciation of the need understand lived experience people accessing care support, including living dementia, their carers supporters. This article describes process value co-production, used alongside principles appreciative inquiry evidence-informed practice, as an approach developing strategic workforce framework, aimed at access Allied Health Professionals (AHPs) for dementia carers....
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at glance that was extracted from about 200 leading journals. To access of an article which published elsewhere, please select “Full Text” option. The original trackable via the “References”
Malignant hyperthermia (MH) is an uncommon, autosomal dominant disorder of skeletal muscle, triggered by inhalational anaesthetics or depolarizing muscle relaxants. Masseter rigidity (MMR) can be regarded as potentially a preceding sign for MH reaction. Susceptibility to determined the in vitro contracture test (IVCT) DNA analysis where familial variant known. Our aims were review patients with MMR, IVCT and had been undertaken, determine if could used initial screening tool susceptibility,...