A5011655475- Neuroscience and Neuropharmacology Research
- Molecular Sensors and Ion Detection
- Enzyme Structure and Function
- Receptor Mechanisms and Signaling
- Cancer therapeutics and mechanisms
- Immune Response and Inflammation
- Ion Channels and Receptors
- Chemical Synthesis and Analysis
- Biochemical and Molecular Research
- Antibiotic Resistance in Bacteria
- Cytokine Signaling Pathways and Interactions
- Protein Kinase Regulation and GTPase Signaling
- Bioactive Compounds and Antitumor Agents
- Monoclonal and Polyclonal Antibodies Research
- Ion channel regulation and function
- Hormonal Regulation and Hypertension
- Macrophage Migration Inhibitory Factor
- Protein Structure and Dynamics
- Neutropenia and Cancer Infections
- Electrolyte and hormonal disorders
- Biochemical Analysis and Sensing Techniques
- Computational Drug Discovery Methods
- Quinazolinone synthesis and applications
- Plant Pathogenic Bacteria Studies
- Ginseng Biological Effects and Applications
University of Hertfordshire
2024
Pharmaron (United Kingdom)
2024
Merck & Co., Inc., Rahway, NJ, USA (United States)
2010-2020
Redx Pharma (United Kingdom)
2016-2020
Macclesfield College
2020
NHS Lanarkshire
2010-2016
Merck (United Kingdom)
2010-2015
University of Strathclyde
2010
University of Glasgow
1996-2003
Cancer Research UK Scotland Institute
1996
Abstract Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading constitutive receptor activation were confined triple-negative breast cancers (TNBC; 6 66 tumors). TNBC cell lines with associated high levels activated (N1-ICD) sensitive the gamma-secretase inhibitor (GSI) MRK-003, both alone combination paclitaxel, vitro vivo, whereas resistant GSI. Immunohistochemical staining N1-ICD xenografts...
Shikimate dehydrogenase catalyzes the fourth step of shikimate pathway, essential route for biosynthesis aromatic compounds in plants and microorganisms. Absent metazoans, this pathway is an attractive target nontoxic herbicides drugs. Escherichia coli expresses two paralogs, NADP-specific AroE a putative enzyme YdiB. Here we characterize YdiB as dual specificity quinate/shikimate that utilizes either NAD or NADP cofactor. Structures with bound cofactors were determined at 1.5 2.5 Å...
Abstract Shikimate kinase, despite low sequence identity, has been shown to be structurally a member of the nucleoside monophosphate (NMP) kinase family, which includes adenylate kinase. In this paper we have explored roles residues in P‐loop shikimate forms binding site for nucleotides and is one most conserved structural features proteins. common with many members contains cysteine residue 2 amino acids upstream essential lysine residue; side chains these are form an ion pair. The C13S...
Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, selective inhibition activity protein represents attractive target for treatment inflammatory diseases. A series 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to 5-position pyrazolopyrimidine ring 3-position pyrazole ring. Replacement substituents responsible poor permeability improvement physical...
ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTPositive Allosteric Modulators of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) ReceptorSimon J. A. Grove, Craig Jamieson*, John K. F. Maclean, Morrow, and Zoran RankovicView Author Information Merck Research Laboratories, MSD Ltd., Newhouse, Motherwell, Lanarkshire ML1 5SH, U.K.*To whom correspondence should be addressed. Current address: Department Pure Applied Chemistry, University Strathclyde, 295 Cathedral Street, Glasgow, G1...
The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated more than 30% human cancers. Specific BRAF MEK inhibitors have shown clinical efficacy patients for treatment BRAF-mutant melanoma. However, majority responses are transient, resistance often associated with reactivation ERK signal pathway. Acquired to these agents has led greater interest ERK, downstream target MAPK De novo design efforts novel scaffold derived from SCH772984 by...
The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment autoimmune diseases. nuclear hormone receptor RORγt is a master regulator cells affects production host cytokines, including IL-17A, IL-17F, IL-22, IL-26, GM-CSF. Substantial interest been spurred across both academia industry to seek small molecules suitable inhibition. A variety inhibitors have reported in past few years, majority which are orthosteric...
We report the discovery of a benzimidazole series CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent inhibition, high selectivity versus related CYP targets, good pharmacokinetic properties in rat rhesus. In rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
Histone deacetylases (HDACs) play diverse roles in many diseases including cancer, sarcopenia, and Alzheimer's. Different isoforms of HDACs appear to disparate the cell are associated with specific diseases; as such, a substantial effort has been made develop isoform-selective HDAC inhibitors. Our group focused on developing HDAC1/HDAC2-specific inhibitors cancer therapeutic. In course characterizing mechanism inhibition novel HDAC1/2-selective inhibitor, it was determined that did not...
Objective: To examine how observed medication nonadherence to 2 second-line, oral anticancer medications (axitinib and everolimus) affects progression-free survival (PFS) among patients with renal cell carcinoma. Methods: We used an adherence–exposure–outcome model simulate the impact of adherence on PFS. Using a pharmacokinetic/pharmacodynamic (PK/PD) population model, we simulated drug exposure measured by area under plasma concentration–time curve (AUC) minimum blood or trough...