Paul A Brough

• Vernalis

The development of more effective drugs requires knowledge of 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 directly in living cells. However, the target molecule may be NMR-invisible due to...

Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit t...

Pyruvate dehydrogenase kinase (PDK) is a pivotal enzyme in cellular energy metabolism that has previously been implicated in cancer through both RNAi based studies and clinical correlations with poor prognosis in several cancer types. Here, we report the discovery of a novel and selective ATP competitive pan-isoform inhibitor of PDK, VER-246608. Co...

The dissociation rate constant kd (off-rate) is the component of ligand-protein binding with the most significant potential to enhance compound potency. Here we provide theoretical and empirical data to show that this parameter can be determined accurately from unpurified reaction products containing designed test compounds. This screening protocol...

Pyruvate dehydrogenase kinase (PDK) regulates the activity of the pyruvate dehydrogenase complex (PDC) through phosphorylation of three serine residues on the E1α subunit, resulting in decreased activity. The expression of all four mammalian isoforms of PDK have been shown to be up-regulated either under tumour relevant conditions (PDK-1 & PDK-3 by...

This book aims to provide a comprehensive examination of the field of molecular chaperone inhibition and its application to pharmaceutical research. With several small molecule inhibitors in oncology clinical development, there is clearly intense interest in the chaperones as a molecular target. Filling a significant gap in the market by providing...

Compounds of formula (I) are inhibitors of fatty acid amide hydrolase, (FAAH), and which are useful in the treatment of diseases or medical conditions which benefit from inhibition of FAAH activity, such as anxiety, depression pain, inflammation, and eating, sleep, neurodegenerative and movement disorders: Formula (I) Wherein Ar1 is optionally subs...

Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray...

We have previously reported the structure-based optimisation of a number of series of potent compounds progressed as clinical candidates for oncology through inhibition of the ATPase activity of the molecular chaperone, Hsp90. The starting point for these candidates was compounds discovered using a combination of structure-based hit identification...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

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 involved in cell proliferation, survival, and transformation. Through its ability to modulate multiple pathways involved in oncogenesis, Hsp90 has generated considerabl...

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based a...

We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (K(d) = 1.7 nmol/L) and proliferation of human tumor cells with GI(50) values of approximately 2 to 40 nmol/L, inducing G(1)-G(2) arrest and apoptosis. Activity is independent of NQO1/...

Heat shock protein (Hsp90) inhibitors are an increasingly interesting and important class of compounds where the first in class, natural product derived inhibitors such as 17-allylaminogeldanamycin (17-AAG), are entering late stage clinical development. Recently the emergence of synthetic, small molecule inhibitors has been described and both NVP-A...

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this serie...

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 the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole am...

Heat shock protein (Hsp)90 is a molecular chaperone that is responsible for the correct folding of a large number of proteins, which allows these proteins to achieve their functional conformation. Client proteins of Hsp90 include many overexpressed or mutated oncogenes that are known to be critical for the transformed phenotype observed in tumors....

Information from X-ray crystal structures of Hsp90 inhibitors bound to the human Hsp90 molecular chaperone was used to assist in the design of 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as novel inhibitors of Hsp90. Accessing an extra interaction with the protein via Phe138 gave a significant increase in binding potency compared to si...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

This review explains why the chaperone Hsp90 is an exciting protein target for the discovery of new drugs to treat cancer in the clinic, and summarises the properties of natural product derived inhibitors before relating the discovery and current state of development of synthetic pyrazole compounds. Blockade of Hsp90 results in reduced cellular lev...

Docking-based virtual screening identified 1-(2-phenol)-2-naphthol compounds as a new class of Hsp90 inhibitors of low to sub-micromolar potency. Here we report the binding affinities and cellular activities of several members of this class. A high resolution crystal structure of the most potent compound reveals its binding mode in the ATP binding...

The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmacodynamic changes. Compound 11 (VER-49009) c...

[122-04-3] C7H4ClNO3 (MW 185.57) InChI = 1S/C7H4ClNO3/c8-7(10)5-1-3-6(4-2-5)9(11)12/h1-4HInChIKey = SKDHHIUENRGTHK-UHFFFAOYSA-N(characterization of amines and alcohols by formation of crystalline amide and ester derivatives; forms suitable directing group for glycosidation reactions)Physical Data: mp 72–74 °C; bp 202–205 °C/105 mmHg.Solubility: sol...

[610-14-0] C7H4ClNO3 (MW 185.57) InChI = 1S/C7H4ClNO3/c8-7(10)5-3-1-2-4-6(5)9(11)12/h1-4HInChIKey = BWWHTIHDQBHTHP-UHFFFAOYSA-N(acylating agent in reaction with amines and alcohols; produces crystalline esters from alcohols; building block for the synthesis of several classes of heterocycles)Physical Data: mp 17–20 °C; bp 148–149 °C/9 mmHg; d 1.404...

2-[125I]Iodomelatonin binding studies were carried out in chick brain membranes to compare the high-affinity melatonin receptor pharmacology of various 2-phenylmelatonin-based compounds, the naphthalenic agonist S-20098, and melatonin. Competition binding studies with 2-phenylmelatonin revealed a single class of binding sites with an inhibitory con...

Two 11C-labelled melatonin derivatives, 2-iodo-[11C]melatonin (2-iodo-5-methoxy-N[11C-acetyl]-tryptamine, an agonist) and 2-phenyl-[11C]melatonin (2-phenyl-5-methoxy-N[11C-acetyl]tryptamine, a putative antagonist) were synthesized from [11C]carbon dioxide. The reaction sequence was common to both compounds and consisted of three steps: (i) carbonyl...

The melatonin analog, 2-phenylmelatonin, has been reported to act as either an agonist or antagonist in various biological systems. In order to further clarify the pharmacological properties of this compound, its effects on melatonin signalling in the rat hypothalamus were examined. As expected, melatonin (10-11-10-8 M) inhibited forskolin-stimulat...

LDA treatment of 2-silylated benzamides 1 affords 2-fluorosilylated acetophenones 3 in a general process likely driven by CIPE-facilitated α-silyl carbanion formation and rearrangement (Scheme 3); oxidation (H2O2) of the products gives 2-hydroxyacetophenones and catechols (Scheme 4).

(+)-Anatoxin-a is a neurotoxic alkaloid produced by the cyanobacterium Anabaena flos-aquae. In this study synthetic (+/-)-anatoxin-a was tested on isolated bovine adrenal chromaffin cells to determine its ability to evoke secretion of endogenous catecholamines through neuronal-type nicotinic receptor activation. Anatoxin-a was found to act as a pot...

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 nicotinic acetylcholine receptors. Racemic anatoxin-a and a series of three analogues with one or more methine or methylene units added...

The production of cyanobacterial toxins as anatoxin-a in the UK by blue-green algae such as Oscillatoria and Anabaena flos-aquae is a potential health hazard, especially to animals, birds and fish. A sensitive reversed-phase ion-pair high-performance liquid chromatographic (RP-HPLC) method is described for the measurement of the neurotoxins anatoxi...

2-Acetyl-9-azabicyclo[4.2.1]nonan-3-one 2(‘hydroxyanatoxin-a’), which represents a conformationally locked variant of the s-cis conformer of the potent cholinergic agonist anatoxin-a, is synthesised and characterised; this molecule lacks both nicotinic and muscarinic potency.