Barry V L Potter

University of Bath, Bath, England, United Kingdom

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Publications (545)2180.21 Total impact

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    ABSTRACT: The inositol polyphosphate 5-phosphatase INPP5B hydrolyzes the 5-phosphate group from water- and lipid-soluble signaling messengers. Two synthetic benzene and biphenyl polyphosphates (BzP/BiPhPs), simplified surrogates of inositol phosphates and phospholipid headgroups, were identified by thermodynamic studies as potent INPP5B ligands. The X-ray structure of the complex between INPP5B and biphenyl 3,3, 4,4, 5,5-hexakisphosphate [BiPh(3,3, 4,4, 5,5)P6, IC50 5.5 µM] was determined at 2.89Å resolution. One inhibitor pole locates in the phospholipid headgroup binding site and the second solvent-exposed ring binds to the His-Tag of another INPP5B molecule, while a molecule of inorganic phosphate is also present in the active site. Benzene 1,2,3-trisphosphate [Bz(1,2,3)P3] [one ring of BiPh(3,3, 4,4, 5,5)P6] inhibits INPP5B ca 6-fold less potently. Co-crystallization with benzene 1,2,4,5-tetrakisphosphate [Bz(1,2,4,5)P4, IC50 = 6.3 µM] yielded a structure refined at 2.9Å resolution. Conserved residues among the 5-phosphatase family mediate similar interactions with Bz(1,2,4,5)P4 and BiPh(3,3',4,4',5,5')P6 to those with the polar groups present in positions 1,4,5 and 6 on the inositol ring of the substrate. 5-Phosphatase specificity most likely resides in the variable zone located close to the 2- and 3-positions of the inositol ring. We propose that the inorganic phosphate present in the INPP5BBiPh(3,3, 4,4, 5,5)P6 complex mimics the post-cleavage substrate 5-phosphate released by INPP5B in the catalytic site, allowing elucidation of two new key features in the catalytic mechanism proposed for the family of phosphoinositide 5-phosphatases: first, the involvement of the conserved Arg-451 in the interaction with the 5-phosphate and secondly, identification of the water molecule that initiates 5-phosphate hydrolysis. Our model has implications for the proposed "moving metal" mechanism. .
    No preview · Article · Feb 2016 · Biochemistry
  • Mark P. Thomas · Stephen J. Mills · Barry V. L. Potter
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    ABSTRACT: Cell signaling via inositol phosphates, in particular via the second messenger myo-inositol 1,4,5-trisphosphate, and phosphoinositides comprises a huge field of biology. Of the nine 1,2,3,4,5,6-cyclohexanehexol isomers, myo-inositol is pre-eminent, with "other" inositols (cis-, epi-, allo-, muco-, neo-, L-chiro-, D-chiro-, and scyllo-) and derivatives rarer or thought not to exist in nature. However, neo- and D-chiro-inositol hexakisphosphates were recently revealed in both terrestrial and aquatic ecosystems, thus highlighting the paucity of knowledge of the origins and potential biological functions of such stereoisomers, a prevalent group of environmental organic phosphates, and their parent inositols. Some "other" inositols are medically relevant, for example, scyllo-inositol (neurodegenerative diseases) and D-chiro-inositol (diabetes). It is timely to consider exploration of the roles and applications of the "other" isomers and their derivatives, likely by exploiting techniques now well developed for the myo series.
    No preview · Article · Dec 2015 · Angewandte Chemie International Edition
  • Mark P. Thomas · Stephen J. Mills · Barry V. L. Potter

    No preview · Article · Dec 2015
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    ABSTRACT: Background: Both the number and size of tumours in NF1 patients increase in response to the rise in steroid hormones seen at puberty and during pregnancy. The size of tumours decreases after delivery, suggesting that hormone-targeting therapy might provide a viable new NF1 treatment approach. Our earlier studies demonstrated that human NF1 tumour cell lines either went through apoptosis or ceased growth in the presence of 2-methoxyoestradiol (2ME2), a naturally occurring anticancer metabolite of 17-β estradiol. Previous reports of treatment with sulfamoylated steroidal and non-steroidal derivatives of 2ME2 showed promising reductions in tumour burden in hormone-responsive cancers other than NF1. Here we present the first studies indicating that 2ME2 derivatives could also provide an avenue for treating NF1, for which few treatment options are available. Methods: STX3451, (2-(3-Bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline), a non-steroidal sulphamate analogue of 2ME2, was tested in dose-dependent studies of malignant and benign NF1 human tumour cell lines and cell lines with variable controlled neurofibromin expression. The mechanisms of action of STX3451 were also analysed. Results: We found that STX3451-induced apoptosis in human malignant peripheral nerve sheath tumour (MPNST) cell lines, even in the presence of elevated oestrogen and progesterone. It inhibits both PI3 kinase and mTOR signalling pathways. It disrupts actin- and microtubule-based cytoskeletal structures in cell lines derived from human MPNSTs and in cells derived from benign plexiform neurofibromas. STX3451 selectively kills MPNST-derived cells, but also halts growth of other tumour-derived NF1 cell lines. Conclusion: STX3451 provides a new approach for inducing cell death and lowering tumour burden in NF1 and other hormone-responsive cancers with limited treatment options.
    Full-text · Article · Oct 2015 · British Journal of Cancer
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    ABSTRACT: Tumor neo-angiogenesis is regulated, in part, by the hypoxia-inducible gene HIF1. Evidence suggests HIF1 associates with polymerized microtubules and traffics to the nucleus. This study investigated the role of HIF1 in mediating the antitumor activity of two steroid-based sulfamate ester microtubule disruptors, STX140 and STX243, in vitro and in vivo. The effects of STX140, STX243 and the parental compound 2-methoxyestradiol (STX66) on HIF1α and HIF2α protein expression were assessed in vitro in MCF-7 and MDA-MB-231 cells cultured under hypoxia. More pertinently, their effects were examined on HIF1-regulated genes in vivo in mice bearing MCF-7 or MDA-MB-231 tumors. The level of mRNA expression of vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUTI), phosphoglycerate kinase (PGK), ATP-binding cassette sub-family B member 1 (ABCB1) and carbonic anhydrase IX (CAIX) was quantified by Real-time Polymerase Chain Reaction (RT-PCR). Despite inhibiting nuclear HIF1α protein accumulation under hypoxia in vitro, STX140 and STX243 did not significantly regulate the expression of four out of five HIF1α-regulated genes in vitro and in vivo. Only CAIX mRNA expression was down-regulated both in vitro and in vivo. Immunoblot analysis showed that STX140 and STX243 reduced CAIX protein expression in vitro. These compounds had no effect on HIF2α translocation. The potential for inhibition of CAIX by STX140 and STX243 was examined by docking the ligands to the active site in comparison with a known sulfamate-based inhibitor. Microtubule disruption and antitumor activity of STX140 and STX243 is most likely HIF1-independent and may, at least in part, be mediated by inhibition of CAIX expression and activity.
    No preview · Article · Oct 2015 · Anticancer research
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    Andrew M Riley · Huanchen Wang · Jeremy Weaver · Barry V. L. Potter
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    ABSTRACT: To synthesise stabilised mimics of InsP8, the most phosphorylated inositol phosphate signalling molecule in Nature, we replaced its two diphosphate (PP) groups with either phosphonoacetate (PA) or methylenebisphosphonate (PCP) groups. Utility of the PA and PCP analogues was verified by structural and biochemical analyses of their interactions with enzymes of InsP8 metabolism.
    Full-text · Article · Jul 2015 · Chemical Communications
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    ABSTRACT: Synthetic compounds open up new avenues to interrogate and manipulate intracellular Ca2+ signalling pathways. They may ultimately lead to drug-like analogues to intervene in disease. Recent advances in chemical biology tools available to probe Ca2+ signalling are described, with a particular focus on those synthetic analogues from our group that have enhanced biological understanding or represent a step towards more drug-like molecules. Adenophostin (AdA) is the most potent known agonist at the inositol 1,4,5-trisphosphate receptor (IP3R) and synthetic analogues provide a binding model for receptor activation and channel opening. 2-O-Modified inositol 1,4,5-trisphosphate (IP3) derivatives that are partial agonists at the IP3R reveal key conformational changes of the receptor upon ligand binding. Biphenyl polyphosphates illustrate that simple non-inositol surrogates can be engineered to give prototype IP3R agonists or antagonists and act as templates for protein co-crystallization. Cyclic adenosine 5'-diphosphoribose (cADPR) can be selectively modified using total synthesis, generating chemically and biologically stable tools to investigate Ca2+ release via the ryanodine receptor (RyR) and to interfere with cADPR synthesis and degradation. The first neutral analogues with a synthetic pyrophosphate bioisostere surprisingly retain the ability to release Ca2+, suggesting a new route to membrane-permeant tools. Adenosine 5'-diphosphoribose (ADPR) activates the Ca2+-, Na+- and K+-permeable transient receptor potential melastatin 2 (TRPM2) cation channel. Synthetic ADPR analogues provide the first structure-activity relationship (SAR) for this emerging messenger and the first functional antagonists. An analogue based on the nicotinic acid motif of nicotinic acid adenine dinucleotide phosphate (NAADP) antagonizes NAADP-mediated Ca2+ release in vitro and is effective in vivo against induced heart arrhythmia and autoimmune disease, illustrating the therapeutic potential of targeted small molecules.
    No preview · Article · Jun 2015 · Biochemical Society Transactions
  • Mark P Thomas · Barry V L Potter
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    ABSTRACT: In 1994, following work from this laboratory, it was reported that estrone-3-O-sulfamate irreversibly inhibits a new potential hormone-dependent cancer target steroid sulfatase (STS). Subsequent drug discovery projects were initiated to develop the core aryl O-sulfamate pharmacophore that, over some twenty years, have led to steroidal and non-steroidal drugs in numerous pre-clinical and clinical trials, with promising results in oncology and women's health, including endometriosis. Drugs have been designed to inhibit STS e.g. Irosustat, as innovative dual-targeting aromatase-steroid sulfatase inhibitors (DASIs) and as multi-targeting agents for hormone-independent tumors, such as the steroidal STX140 and non-steroidal counterparts, acting inter alia through microtubule disruption. The aryl sulfamate pharmacophore is highly versatile, operating via three distinct mechanisms of action and imbues attractive pharmaceutical properties. This Perspectives article gives a personal view of the work leading both to the therapeutic concepts and these drugs, their current status and how they might develop in the future.
    No preview · Article · May 2015 · Journal of Medicinal Chemistry
  • Mark P. Thomas · Barry V.L. Potter
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    ABSTRACT: Estrogen sulfamate derivatives were the first irreversible active-site-directed inhibitors of steroid sulfatase (STS), an emerging drug target for endocrine therapy of hormone dependent diseases that catalyses inter alia the hydrolysis of estrone sulfate to estrone. In recent years this has stimulated clinical investigation of the estradiol derivative both as an oral prodrug and its currently ongoing exploration in endometriosis. 2-Substituted steroid sulfamate derivatives show considerable potential as multi-targeting agents for hormone-independent disease, but are also potent STS inhibitors. The steroidal template has spawned nonsteroidal STS inhibitors one of which, Irosustat, has been evaluated clinically in breast cancer, endometrial cancer and prostate cancer and there is potential for innovative dual-targeting approaches. This review surveys the role of estrogen sulfamates, their analogues and current status. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Apr 2015 · The Journal of steroid biochemistry and molecular biology
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    ABSTRACT: Here we describe the successful synthesis of cyclic ADP-4-thioribose (cADPtR, 3), designed as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger, in which the key N1-β-thioribosyladenosine structure was stereoselectively constructed by condensation between the imidazole nucleoside derivative 8 and the 4-thioribosylamine 7 via equilibrium in 7 between the α-anomer (7α) and the β-anomer (7β) during the reaction course. cADPtR is, unlike cADPR, chemically and biologically stable, while it effectively mobilizes intracellular Ca2+ like cADPR in various biological systems, such as sea urchin homogenate, NG108-15 neuronal cells, and Jurkat T-lymphocytes. Thus, cADPtR is a stable equivalent of cADPR, which can be useful as a biological tool for investigating cADPR-mediated Ca2+-mobilizing pathways.
    No preview · Article · Dec 2014
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    ABSTRACT: Cyclic adenosine 5'-diphosphate ribose (cADPR) analogs based on the cyclic inosine 5'-diphosphate ribose (cIDPR) template were synthesized by recently developed stereo- and regioselective N1-ribosylation. Replacing the base N9-ribose with a butyl chain generates inhibitors of cADPR hydrolysis by the human ADP-ribosyl cyclase CD38 catalytic domain (shCD38), illustrating the non-essential nature of the "southern" ribose for binding. Butyl substitution generally improves potency relative to the parent cIDPRs and 8-amino¬-N9-butyl-cIDPR is comparable to the best non-covalent CD38 inhibitors to date (IC50 3.3 μM). Crystallographic analysis of the shCD38:8-amino¬-N9-butyl-cIDPR complex to a 2.05Å resolution unexpectedly reveals an N1-hydrolyzed ligand in the active site, suggesting that it is the N6-imino form of cADPR that is hydrolyzed by CD38. While HPLC studies confirm ligand cleavage at very high protein concentrations, they indicate that hydrolysis does not occur under physiological concentrations. Taken together, these analogs confirm that the "northern" ribose is critical for CD38 activity and inhibition, provide new insight into the mechanism of cADPR hydrolysis by CD38 and may aid future inhibitor design.
    Full-text · Article · Sep 2014 · Journal of Medicinal Chemistry
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    ABSTRACT: Background: STX2484 is a novel non-steroidal compound with potent anti-proliferative activity. These studies aimed to identify STX2484's mechanism of action, in vivo efficacy and activity in taxane-resistant breast cancer models. Methods: Effects of STX2484 and paclitaxel on proliferation, cell cycle and apoptosis were assessed in vitro in drug-resistant (MCF-7DOX) and non-resistant cells (MCF-7WT). STX2484 efficacy in βIII tubulin overexpression in MCF-7 cells was also determined. Anti-angiogenic activity was quantified in vitro by a co-culture model and in vivo using a Matrigel plug assay. An MDA-MB-231 xenograft model was used to determine STX2484 efficacy in vivo. Results: STX2484 is a tubulin disruptor, which induces p53 expression, Bcl2 phosphorylation, caspase-3 cleavage, cell cycle arrest and apoptosis. In addition, STX2484 is a potent anti-angiogenic agent in vitro and in vivo. In breast cancer xenografts, STX2484 (20 mg kg−1 p.o.) suppressed tumour growth by 84% after 35 days of daily dosing, with limited toxicity. In contrast to paclitaxel, STX2484 efficacy was unchanged in two clinically relevant drug-resistant models. Conclusions: STX2484 is an orally bioavailable microtubule-disrupting agent with in vivo anti-angiogenic activity and excellent in vivo efficacy with no apparent toxicity. Crucially, STX2484 has superior efficacy to paclitaxel in models of clinical drug resistance.
    Full-text · Article · Jun 2014 · British Journal of Cancer
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    Joanna M Swarbrick · Barry V L Potter
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    ABSTRACT: Cyclic adenosine 5'-diphosphate ribose (cADPR) is a potent calcium-releasing second messenger. Sensitive, functional tools suitable for biological studies are essential to interrogate the mechanism by which cADPR is formed, how it interacts with its biological target, and ultimately towards intervention in disease states. A click-mediated macrocyclisation was employed to generate the first neutral cADPR analogues containing a 1,4-triazole bioisostere. Surprisingly, the ability to release Ca 2+ was retained, and hydrolysis of cADPR by CD38 was also inhibited, illustrating the potential of this approach to design more drug-like signalling pathway modulators. Using crystal structure complexes to identify critical binding motifs, further cyclic and simple low molecular weight inhibitors of cADPR hydrolysis were designed.
    Full-text · Conference Paper · Jun 2014
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    ABSTRACT: Tetrahydroisoquinoline (THIQ)-based “chimeric” microtubule disruptors were optimised through modification of the N-benzyl motif, in concert with changes at C3 and C7, resulting in the identification of compounds with improved in vitro antiproliferative activities (e.g. 15: GI50 20 nM in DU-145). The broad anticancer activity of these novel structures was confirmed in the NCI 60-cell line assay, with 12 e,f displaying MGM values in the 40 nM region. In addition, their profiles as inhibitors of tubulin polymerisation and colchicine binding to tubulin were confirmed. Compound 15, for example, inhibited tubulin polymerisation with an IC50 of 1.8 μM, close to that of the clinical drug combretastatin A-4, and also proved effective at blocking colchicine binding. Additionally, compound 20 b was identified as the only phenol in the series to date showing both better in vitro antiproliferative properties than its corresponding sulfamate and excellent antitubulin data (IC50=1.6 μM). Compound 12 f was selected for in vivo evaluation at the NCI in the hollow fibre assay and showed very good activity and wide tissue distribution, illustrating the value of this template for further development.
    No preview · Article · May 2014 · ChemMedChem
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    ABSTRACT: Diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) is one of the mammalian PPIP5K isoforms responsible for synthesis of diphosphoinositol polyphosphates (inositol pyrophosphates; PP-InsPs), regulatory molecules that function at the interface of cell signaling and organismic homeostasis. The development of drugs that inhibit PPIP5K2 could have both experimental and therapeutic applications. Here, we describe a synthetic strategy for producing naturally occurring 5-PP-InsP4, as well as several inositol polyphosphate analogs, and we study their interactions with PPIP5K2 using biochemical and structural approaches. These experiments uncover an additional ligand-binding site on the surface of PPIP5K2, adjacent to the catalytic pocket. This site facilitates substrate capture from the bulk phase, prior to transfer into the catalytic pocket. In addition to demonstrating a "catch-and-pass" reaction mechanism in a small molecule kinase, we demonstrate that binding of our analogs to the substrate capture site inhibits PPIP5K2. This work suggests that the substrate-binding site offers new opportunities for targeted drug design.
    No preview · Article · Apr 2014 · Chemistry & biology
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    ABSTRACT: A SAR translation strategy adopted for the discovery of tetrahydroisoquinolinone (THIQ)-based steroidomimetic microtubule disruptors has been extended to dihydroisoquinolinone (DHIQ)-based compounds. A steroid A,B-ring-mimicking DHIQ core was connected to methoxyaryl D-ring mimics through methylene, carbonyl, and sulfonyl linkers, and the resulting compounds were evaluated against two cancer cell lines. The carbonyl-linked DHIQs in particular exhibit significant in vitro antiproliferative activities (e.g., 6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydroisoquinolin-1(2H)-one (16 g): GI50 51 nM in DU-145 cells). The broad anticancer activity of DHIQ 16 g was confirmed in the NCI 60-cell line assay giving a mean activity of 33 nM. Furthermore, 6-hydroxy-2-(3,5-dimethoxybenzoyl)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (16 f) and 16 g and their sulfamate derivatives 17 f and 17 g (2-(3,5-dimethoxybenzoyl)-7-methoxy-6-sulfamoyloxy-3,4-dihydroisoquinolin-1(2H)-one and 7-methoxy-2-(3,4,5-trimethoxybenzoyl)-6-sulfamoyloxy-3,4-dihydroisoquinolin-1(2H)-one, respectively) show excellent activity against the polymerization of tubulin, close to that of the clinical combretastatin A-4, and bind competitively at the colchicine binding site of tubulin. Compounds 16 f and 17 f were also shown to demonstrate in vitro anti-angiogenic activity. Additionally, X-ray and computational analyses of 17 f reveal that electrostatic repulsion between the two adjacent carbonyl groups, through conformational biasing, dictates the adoption of a “steroid-like” conformation that may partially explain the excellent in vitro activities.
    Full-text · Article · Apr 2014 · ChemMedChem
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    ABSTRACT: The pattern recognition receptor RIG-I is critical for Type-I interferon production. However, the global regulation of RIG-I signaling is only partially understood. Using a human genome-wide RNAi-screen, we identified 226 novel regulatory proteins of RIG-I mediated interferon-β production. Furthermore, the screen identified a metabolic pathway that synthesizes the inositol pyrophosphate 1-IP7 as a previously unrecognized positive regulator of interferon production. Detailed genetic and biochemical experiments demonstrated that the kinase activities of IPPK, PPIP5K1 and PPIP5K2 (which convert IP5 to1-IP7) were critical for both interferon induction, and the control of cellular infection by Sendai and influenza A viruses. Conversely, ectopically expressed inositol pyrophosphate-hydrolases DIPPs attenuated interferon transcription. Mechanistic experiments in intact cells revealed that the expression of IPPK, PPIP5K1 and PPIP5K2 was needed for the phosphorylation and activation of IRF3, a transcription factor for interferon. The addition of purified individual inositol pyrophosphates to a cell free reconstituted RIG-I signaling assay further identified 1-IP7 as an essential component required for IRF3 activation. The inositol pyrophosphate may act by β-phosphoryl transfer, since its action was not recapitulated by a synthetic phosphonoacetate analogue of 1-IP7. This study thus identified several novel regulators of RIG-I, and a new role for inositol pyrophosphates in augmenting innate immune responses to viral infection that may have therapeutic applications.
    Full-text · Article · Feb 2014 · PLoS Pathogens
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    ABSTRACT: The syntheses and antiproliferative activities of novel substituted tetrahydroisoquinoline derivatives and their sulfamates are discussed. Biasing of conformational populations through substitution on the tetrahydroisoquinoline core at C1 and C3 has a profound effect on the antiproliferative activity against various cancer cell lines. The C3 methyl-substituted sulfamate (±)-7-methoxy-2-(3-methoxybenzyl)-3-methyl-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (6 b), for example, was found to be ∼10-fold more potent than the corresponding non-methylated compound 7-methoxy-2-(3-methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (4 b) against DU-145 prostate cancer cells (GI50 values: 220 nM and 2.1 μM, respectively). Such compounds were also found to be active against a drug-resistant MCF breast cancer cell line. The position and nature of substitution of the N-benzyl group in the C3-substituted series was found to have a significant effect on activity. Whereas C1 methylation has little effect on activity, introduction of C1 phenyl and C3-gem-dimethyl substituents greatly decreases antiproliferative activity. The ability of these compounds to inhibit microtubule polymerisation and to bind tubulin in a competitive manner versus colchicine confirms the mechanism of action. The therapeutic potential of a representative compound was confirmed in an in vivo multiple myeloma xenograft study.
    No preview · Article · Feb 2014 · ChemMedChem
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    ABSTRACT: Analogues of the potent Ca(2+) releasing second messenger cyclic ADP-ribose (cADPR) with a 1,2,3-triazole pyrophosphate bioisostere were synthesised by click-mediated macrocyclisation. The ability to activate Ca(2+) release was surprisingly retained, and hydrolysis of cADPR by CD38 could also be inhibited, illustrating the potential of this approach to design drug-like signalling pathway modulators.
    Full-text · Article · Jan 2014 · Chemical Communications
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    Andrew M Riley · Sabine Windhorst · Hong-Yin Lin · Barry V L Potter
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    ABSTRACT: When applied extracellularly, myo-inositol hexakisphosphate (InsP6 ) and myo-inositol pentakisphosphate (InsP5 ) can inhibit the growth and proliferation of tumour cells. There is debate about whether these effects result from interactions of InsP6 and InsP5 with intracellular or extracellular targets. We synthesised FAM-InsP5 , a fluorescent conjugate of InsP5 that allows direct visualisation of its interaction with cells. FAM-InsP5 was internalised by H1229 tumour cells, a finding that supports earlier reports that externally applied inositol phosphates can-perhaps surprisingly-enter into cells. Close examination of the process of FAM-InsP5 uptake suggests a mechanism of non-receptor-mediated endocytosis, which is blocked at 4 °C and probably involves interaction of the ligand with the glycocalyx. However, our results are difficult to reconcile with antiproliferative mechanisms that require direct interactions of externally applied InsP5 or InsP6 with cytosolic proteins, because internalised FAM-InsP5 appears in lysosomes and apparently does not enter the cytoplasm. Studies using FAM-InsP5 are less difficult and time-consuming than experiments using InsP5 or InsP6 , a factor that allowed us to analyse cellular uptake across a range of human cell types, identifying strong cell-specific differences.
    Full-text · Article · Jan 2014 · ChemBioChem

Publication Stats

14k Citations
2,180.21 Total Impact Points

Institutions

  • 1991-2015
    • University of Bath
      • Department of Pharmacy and Pharmacology
      Bath, England, United Kingdom
    • University of Maryland, College Park
      Maryland, United States
  • 1980-2015
    • University of Oxford
      Oxford, England, United Kingdom
  • 2014
    • The University of Hong Kong
      Hong Kong, Hong Kong
  • 1985-2010
    • University of Leicester
      • • Department of Chemistry
      • • Department of Cell Physiology and Pharmacology
      Leiscester, England, United Kingdom
  • 2006-2008
    • Imperial College London
      • • Institute of Reproductive and Developmental Biology
      • • Faculty of Medicine
      London, ENG, United Kingdom
  • 2007
    • University of Florence
      Florens, Tuscany, Italy
  • 1990-2006
    • University of Cambridge
      • Department of Pharmacology
      Cambridge, England, United Kingdom
    • University of California, Davis
      Davis, California, United States
  • 1994
    • University of Birmingham
      • School of Biosciences
      Birmingham, England, United Kingdom
  • 1992
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 1990-1992
    • University of Wisconsin–Madison
      • Department of Medicine
      Madison, Wisconsin, United States
  • 1987
    • MRC National Institute for Medical Research
      Londinium, England, United Kingdom