A5091444038- Heat shock proteins research
- Enzyme Structure and Function
- Endoplasmic Reticulum Stress and Disease
- ATP Synthase and ATPases Research
- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Marine Toxins and Detection Methods
- Cancer, Hypoxia, and Metabolism
- Analytical Chemistry and Chromatography
- Signaling Pathways in Disease
- Synthesis and biological activity
- thermodynamics and calorimetric analyses
- Aquatic Ecosystems and Phytoplankton Dynamics
- Coordination Chemistry and Organometallics
- Ion channel regulation and function
- Nicotinic Acetylcholine Receptors Study
- Plant-based Medicinal Research
- Circadian rhythm and melatonin
- Bioactive Compounds and Antitumor Agents
- Biochemical and Molecular Research
- Biochemical Acid Research Studies
- Photoreceptor and optogenetics research
- Catalytic C–H Functionalization Methods
- Legal principles and applications
- Legal Education and Practice Innovations
Granta Design (United Kingdom)
2005-2024
Novartis (Switzerland)
2007-2010
Novartis Institutes for BioMedical Research
2010
University of Bremen
2009
Institute of Cancer Research
2005-2007
Cancer Research UK
2005-2007
University of Bristol
1994-2001
University of Waterloo
1996-1998
Abstract We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (Kd = 1.7 nmol/L) and proliferation human tumor cells with GI50 values approximately 2 to 40 nmol/L, inducing G1-G2 arrest apoptosis. Activity is independent NQO1/DT-diaphorase, maintained in drug-resistant under hypoxic conditions. The molecular signature inhibition, comprising induced HSP72 depleted client proteins,...
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe structure-based design, synthesis, structure−activity relationships and pharmacokinetics potent small-molecule inhibitors based on 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity Hsp90, measured in a fluorescence polarization (FP) competitive binding assay, active cancer cell lines where they inhibit proliferation exhibit...
The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain molecular chaperone Hsp90 has been used design 5-amide analogues. These exhibit enhanced potency against target in binding and functional assays with accompanying appropriate cellular pharmacodynamic changes. Compound 11 (VER-49009) compares favorably clinically evaluated 17-AAG.
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential therapeutic agents for treatment cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive inhibitors, which were designed by combining structural elements distinct low affinity hits generated from fragment-based and in silico screening exercises concert with information X-ray protein crystallography. Examples this series have high (IC50 = 50−100 nM) measured a fluorescence...
Abstract Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified VER-49009. Here, we describe detailed biological properties VER-49009 corresponding isoxazole VER-50589. X-ray...
The dissociation rate constant kd (off-rate) is the component of ligand-protein binding with most significant potential to enhance compound potency. Here we provide theoretical and empirical data show that this parameter can be determined accurately from unpurified reaction products containing designed test compounds. This screening protocol amenable parallel chemistry, provides efficiencies time materials, complements existing methodologies for hit-to-lead phase in fragment-based drug discovery.
// Jonathan D. Moore 1,2,* , Anna Staniszewska 1,* Terence Shaw 1 Jalanie D’Alessandro Ben Davis Alan Surgenor Lisa Baker Natalia Matassova James Murray Alba Macias Paul Brough Mike Wood and Patrick C. Mahon Vernalis (R&D) Ltd, Granta Park, Cambridge, UK 2 Current address: Horizon discovery, Cambridge Research Waterbeach, * These authors contributed equally to this work Correspondence: Mahon, email: Keywords : Pyruvate dehydrogenase kinase, glycolysis, Warburg metabolism, Nov3r...
Abstract Heat shock protein 90 (Hsp90) is a ubiquitously expressed molecular chaperone with ATPase activity involved in the conformational maturation and stability of key signaling molecules cell proliferation, survival, transformation. Through its ability to modulate multiple pathways oncogenesis, Hsp90 has generated considerable interest as therapeutic target. NVP-BEP800 novel, fully synthetic, orally bioavailable inhibitor that binds NH2-terminal ATP-binding pocket Hsp90. showed against...
Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application structure-based drug design enabled rapid hit lead progression in a program identify pan-isoform ATP-competitive inhibitors PDHK. Lead optimization identified selective sub-100-nM enzyme which significantly...
The development of more effective drugs requires knowledge their bioavailability and binding efficacy directly in the native cellular environment. In-cell nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for investigating ligand–target interactions living cells. However, target molecule may be NMR-invisible due to with components, while observing ligand by 1H NMR impractical background. Such limitations can overcome fluorinated ligands 19F in-cell as they bind intracellular...
The production of cyanobacterial toxins as anatoxin-a in the UK by blue—green algae such Oscillatoria and Anabaena flos-aquae is a potential health hazard, especially to animals, birds fish. A sensitive reversed-phase ion-pair high-performance liquid chromatographic (RP-HPLC) method described for measurement neurotoxins (AnTx) homoanatoxin (HomoAnTx) presence lyophilized algal extract. base-deactivated C18 column material was used with acetonitrile—phosphate buffer (pH 3) sodium dodecyl...
Abstract The potent nicotinic agonist anatoxin‐a has a semi‐rigid structure amenable to chemical synthesis and modification, making it an attractive candidate for exploring the structure‐activity relationships of ligands at acetylcholine receptors. Racemic series three analogues with one or more methine methylene units added acetyl sidechain were synthesised designated homoanatoxin, propylanatoxin, isopropylanatoxin. In competition binding assays on two neuronal receptors in rat brain...
2-Acetyl-9-azabicyclo[4.2.1]nonan-3-one 2('hydroxyanatoxin-a'), which represents a conformationally locked variant of the s-cis conformer potent cholinergic agonist anatoxin-a, is synthesised and characterised; this molecule lacks both nicotinic muscarinic potency.