D R Newell

Newcastle University, Newcastle-on-Tyne, England, United Kingdom

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Publications (191)962.5 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Therapy resistance and associated liver disease make hepatocellular cancers (HCC) difficult to treat with traditional cytotoxic therapies, while newer targeted approaches offer only modest survival benefit. We focused on DNA-dependent protein kinase, DNA-PKcs, encoded by PRKDC and central to DNA damage repair by non-homologous end joining. Our aim was to explore its roles in hepatocarcinogenesis and as a novel therapeutic candidate. Experimental Design: PRKDC was characterised in liver tissues from of 132 patients (normal liver (n=10), cirrhotic liver (n=13), dysplastic nodules (n=18), HCC (n=91)) using Affymetrix U133 Plus 2.0 and 500K Human Mapping SNP arrays (cohort 1). In addition, we studied a case series of 45 patients with HCC undergoing diagnostic biopsy (cohort 2). Histological grading, response to treatment and survival were correlated with DNA-PKcs quantified immunohistochemically. Parallel in vitro studies determined the impact of DNA-PK on DNA repair and response to cytotoxic therapy. Results: Increased PRKDC expression in HCC was associated with amplification of its genetic locus in cohort 1. In cohort 2, elevated DNA-PKcs identified patients with treatment-resistant HCC, progressing at a median of 4.5 months compared to 16.9 months, while elevation of activated pDNA-PK independently predicted poorer survival. DNA-PKcs was high in HCC cell lines, where its inhibition with NU7441 potentiated irradiation and doxorubicin-induced cytoxicity, while the combination suppressed HCC growth in vitro and in vivo. Conclusions: These data identify PRKDC/DNA-PKcs as a candidate driver of hepatocarcinogenesis, whose biopsy characterisation at diagnosis may impact stratification of current therapies, and whose specific future targeting may overcome resistance. Copyright © 2014, American Association for Cancer Research.
    Clinical Cancer Research 12/2014; · 8.19 Impact Factor
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    ABSTRACT: Two libraries of substituted benzimidazoles were designed using a ‘scaffold-hopping’ approach based on reported MDM2-p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X-ray structure. Benzimidazole libraries were prepared using an efficient solution-phase approach, and screened for inhibition of the MDM2-p53 and MDMX-p53 protein-protein interactions. Key examples showed inhibitory activity against both targets.This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 11/2014; · 2.51 Impact Factor
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    ABSTRACT: 0 -deoxy-3 0 -fluorothymidine (FLT) 5 0 -O-glucuronide: a reference standard for imaging studies with [ 18 F]FLT Reaction of methyl 2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl)-a-D-glucopyranuronate with 3 0 -deoxy-3 0 -fluorothymidine in the presence of trimethylsilyl trifluoromethanesulfonate gave (2R,3R,4S,5S,6S)-2-(((2R,3S,5R)-3-fluoro-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)-methoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, which was hydrolysed to 3 0 -deoxy-3 0 -fluorothymidine-5 0 -glucuronide. Analysis of this reference standard by high performance liquid chromatography enabled the identification of [ 18 F]3 0 -deoxy-3 0 -fluorothymidine-5 0 -glucuronide in blood samples from six human patients who had been administered [ 18 F]3 0 -deoxy-3 0 -fluorothymidine.
    Medicinal Chemistry Communication 06/2014; · 2.63 Impact Factor
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    ABSTRACT: Inhibition of DNA repair is an attractive therapeutic approach to enhancing the activity of DNA-damaging anticancer chemotherapeutic agents. Similarly, blockade of the multidrug-resistance protein 1 (MDR1) can overcome efflux-mediated resistance. DNA-dependent protein kinase (DNA-PK) is essential for the non-homologous end-joining DNA repair pathway. NU7441 is a potent DNA-PK inhibitor (IC50=14nM) that is used widely to study the effects of DNA-PK inhibition in vitro. In growth inhibition studies, 1μM NU7441 sensitised vincristine-resistant CCRF-CEM VCR/R leukaemia cells (1200-fold resistant) to a range of MDR1 substrates, including doxorubicin (8-fold, p=0.03), vincristine (14-fold, p=0.01) and etoposide (63-fold, p=0.02), compared with 1.4-fold (p=0.02), 2.2-fold (p=0.04) and 3.6-fold (p=0.01) sensitisation, respectively, in parental CCRF-CEM cells. This difference in NU7441 sensitivity was confirmed in another two parental and MDR1-overexpressing cell line pairs. A doxorubicin fluorescence assay showed that in MDR1-overexpressing canine kidney MDCKII-MDR1 cells, 1μM NU7441 increased doxorubicin nuclear fluorescence 16-fold. NU7441 and 3 structurally-related compounds (NU7742 (an NU7441 analogue that does not inhibit DNA-PK - IC50>10μM), DRN1 (DNA-PK-inhibitory atropisomeric NU7441 derivative - IC50=2nM) and DRN2 (DNA-PK non-inhibitory atropisomeric NU7441 derivative - IC50=7μM)) all increased intracellular vincristine accumulation in the CCRF-CEM VCR/R cells to a level similar to verapamil, as measured by LC-MS. However, the non-inhibitory compound NU7742 was 5-fold less effective at sensitising CCRF-CEM VCR/R cells to vincristine than NU7441 (p=0.008). This paper demonstrates that NU7441 is a dual DNA-PK and MDR1 inhibitor, and this extends the therapeutic potential of the compound when used in combination with MDR substrates.
    Biochemical pharmacology 01/2014; · 4.25 Impact Factor
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    ABSTRACT: Combined targeting of the MAPK and PI3K signalling pathways in cancer may be necessary for optimal therapeutic activity. To support clinical studies of combination therapy, 3'-deoxy-3'-[(18)F]-fluorothymidine ([(18)F]-FLT) uptake measured by Positron Emission Tomography (PET) was evaluated as a non-invasive surrogate response biomarker in pre-clinical models. The in vivo anti-tumour efficacy and PK-PD properties of the MEK inhibitor PD 0325901 and the PI3K inhibitor GDC-0941, alone and in combination, were evaluated in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice, and [(18)F]-FLT PET investigated in mice bearing HCT116 xenografts. Dual targeting of PI3K and MEK induced marked tumour growth inhibition in vivo, and enhanced anti-tumour activity was predicted by [(18)F]-FLT PET scanning after 2 days of treatment. Pharmacodynamic analyses using the combination of the PI3K inhibitor GDC-0941 and the MEK inhibitor PD 0325901 revealed that increased efficacy is associated with an enhanced inhibition of the phosphorylation of ERK1/2, S6 and 4EBP1, compared to that observed with either single agent, and maintained inhibition of AKT phosphorylation. Pharmacokinetic studies indicated that there was no marked PK interaction between the two drugs. Together these results indicate that the combination of PI3K and MEK inhibitors can result in significant efficacy, and demonstrate for the first time that [(18)F]-FLT PET can be correlated to the improved efficacy of combined PI3K and MEK inhibitor treatment.
    PLoS ONE 12/2013; 8(12):e81763. · 3.53 Impact Factor
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    ABSTRACT: Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O6-cyclohexylmethylguanine derivatives, revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a 'reverse' binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these 'reverse' binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited sub-micromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.
    Journal of Medicinal Chemistry 12/2013; · 5.48 Impact Factor
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    ABSTRACT: Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-ylidene)methyl)-2,5-dimethyl-1H-pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile as an MDM2-p53 inhibitor (IC50 = 12.3 μM). MDM2-p53 and MDMX-p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (MDM2 IC50 = 0.11 μM; MDMX IC50 = 4.2 μM) and 5-((1-(4-nitrophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (MDM2 IC50 = 0.15 μM; MDMX IC50 = 4.2 μM), and cellular activity consistent with p53 activation in MDM2 amplified cells. Further SAR studies demonstrated the requirement for the triarylpyrrole moiety for MDMX-p53 activity but not for MDM2-p53 inhibition.
    Medicinal Chemistry Communication 09/2013; 4(9):1297-1304. · 2.63 Impact Factor
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    ABSTRACT: Analogues of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 30 nM), have been synthesized in which water-solubilizing groups [NHCO(CH2)nNR(1)R(2), where n = 1 or 2 and the moiety R(1)R(2)N was derived from a library of primary and secondary amines, e.g. morpholine] were placed at the 1-position. The compounds were obtained by a multiple-parallel approach in which the two heterocyclic precursors were joined by Suzuki-Miyaura cross-coupling. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g. 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC50 = 5.0 ± 1 nM, IR Dose Modification Ratio = 13). Neither homologation of the acetamido linker nor replacement of the acetamido moiety with and an 1-alkoxy or 1-acetyloxy linker resulted in consistently greater DNA-PK inhibition or DMRs. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors with adequate amorphous solubility, as well as lack of hERG inhibition and acceptable plasma protein binding, to warrant further investigation. One of these compounds, 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-1-yl)acetamide (39), was shown to inhibit DNA-PK in cell-based assays and prevent the repair of IR-induced double strand break (DSB). Furthermore, this compound potentiates not only IR in vitro but also DNA -inducing cytotoxic anticancer agents, both in vitro and in vivo.
    Journal of Medicinal Chemistry 07/2013; · 5.48 Impact Factor
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    ABSTRACT: ATM kinase signals DNA double strand breaks (DSB) to cell cycle arrest via p53 and DNA repair. ATM-defective cells are sensitive to DSB-inducing agents, making ATM an attractive target for anticancer chemo- and radio-sensitisation. KU59403 is an ATM inhibitor with the potency, selectivity and solubility for advanced pre-clinical evaluation. KU59403 was not cytotoxic to human cancer cell lines (SW620, LoVo, HCT116 and MDA-MB-231) per se but significantly increased the cytotoxicity of topoisomerase I and II poisons: camptothecin, etoposide and doxorubicin. Chemo- and radio-sensitisation by ATM inhibition was not p53-dependent. Following administration to mice, KU59403 distributed to tissues and concentrations exceeding those required for in vitro activity were maintained for at least 4 hr in tumour xenografts. KU59403 significantly enhanced the antitumour activity of topoisomerase poisons in mice bearing human colon cancer xenografts (SW620 and HCT116) at doses that were non-toxic alone and well tolerated in combination. Chemosensitisation was both dose and schedule-dependent. KU59403 represents a major advance in ATM inhibitor development, being the first compound to demonstrate good tissue distribution and significant chemo-sensitisation in in vivo models of human cancer, without major toxicity. KU59403 provides the first proof-of-principle pre-clinical data to support the future clinical development of ATM inhibitors.
    Molecular Cancer Therapeutics 03/2013; · 5.60 Impact Factor
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    ABSTRACT: Tip60 (KAT5) is a histone acetyltransferase (HAT enzyme) involved in multiple cellular processes including transcriptional regulation, DNA damage repair and cell signalling. In prostate cancer, aggressive cases over-express Tip60 which functions as an androgen receptor co-activator via direct acetylation of lysine residues within the KLKK motif of the receptor hinge region. The purpose of this study was to identify and characterise a Tip60 acetylase inhibitor. High-throughput screening revealed an isothiazole that inhibited both Tip60 and p300 HAT activity. This substance (initially identified as 4-methyl-5-bromoisothiazole) and other isothiazoles were synthesised and assayed against Tip60. Although an authentic sample of 4-methyl-5-bromoisothiazole was inactive against Tip60, in an in vitro HAT assay, 1,2-bis(isothiazol-5-yl)disulfane (NU9056) was identified as a relatively potent inhibitor (IC(50) 2 µM). Cellular activity was confirmed by analysis of acetylation of histone and non-histone proteins in a prostate cancer cell line model. NU9056 treatment inhibited cellular proliferation in a panel of prostate cancer cell lines (50% growth inhibition, 8-27 µM) and induced apoptosis via activation of caspase 3 and caspase 9 in a concentration- and time-dependent manner. Also, decreased androgen receptor, prostate specific antigen, p53 and p21 protein levels were demonstrated in response to treatment with NU9056. Furthermore, pre-treatment with NU9056 inhibited both ATM phosphorylation and Tip60 stabilization in response to ionising radiation. Based on the activity of NU9056 and the specificity of the compound towards Tip60 relative to other HAT enzymes, these chemical biology studies have identified Tip60 as a potential therapeutic target for the treatment of prostate cancer.
    PLoS ONE 10/2012; 7(10):e45539. · 3.53 Impact Factor
  • Molecular Cancer Therapeutics 08/2012; 11(8):1789. · 6.11 Impact Factor
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    ABSTRACT: DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs) is structurally similar to PI-3K, which promotes cell survival and proliferation and is upregulated in many cancers. KU-0060648 is a dual inhibitor of DNA-PK and PI-3K in vitro. KU-0060648 was investigated in a panel of human breast and colon cancer cells. The compound inhibited cellular DNA-PK autophosphorylation with IC(50) values of 0.019 μmol/L (MCF7 cells) and 0.17 μmol/L (SW620 cells), and PI-3K-mediated AKT phosphorylation with IC(50) values of 0.039 μmol/L (MCF7 cells) and more than 10 μmol/L (SW620 cells). Five-day exposure to 1 μmol/L KU-0060648 inhibited cell proliferation by more than 95% in MCF7 cells but only by 55% in SW620 cells. In clonogenic survival assays, KU-0060648 increased the cytotoxicity of etoposide and doxorubicin across the panel of DNA-PKcs-proficient cells, but not in DNA-PKcs-deficient cells, thus confirming that enhanced cytotoxicity was due to DNA-PK inhibition. In mice bearing SW620 and MCF7 xenografts, concentrations of KU-0060648 that were sufficient for in vitro growth inhibition and chemosensitization were maintained within the tumor for at least 4 hours at nontoxic doses. KU-0060648 alone delayed the growth of MCF7 xenografts and increased etoposide-induced tumor growth delay in both in SW620 and MCF7 xenografts by up to 4.5-fold, without exacerbating etoposide toxicity to unacceptable levels. The proof-of-principle in vitro and in vivo chemosensitization with KU-0060648 justifies further evaluation of dual DNA-PK and PI-3K inhibitors.
    Molecular Cancer Therapeutics 05/2012; 11(8):1789-98. · 5.60 Impact Factor
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    ABSTRACT: Combined targeting of MAPK and PI3K signalling pathways may be necessary for optimal therapeutic activity in cancer. This study evaluated the MEK inhibitors AZD6244 and PD0325901, alone and in combination with the dual mTOR/PI3K inhibitor NVP-BEZ235 or the PI3K inhibitor GDC-0941, in three colorectal cancer cell lines. Growth inhibition, survival and signal transduction were measured using the Sulforhodamine B assay, clonogenicity and western blotting, respectively, in HCT116, HT29 and DLD1 cell lines. All MEK/PI3K inhibitor combinations exhibited marked synergistic growth inhibition; however, GDC-0941 displayed greater synergy in combination with either MEK inhibitor. NVP-BEZ235 exhibited stronger inhibition of 4EBP1 phosphorylation, and similar inhibition of S6 and AKT phosphorylation, compared with GDC-0941. Both PD0325901 and AZD6244 inhibited ERK phosphorylation, and with MEK/PI3K inhibitor combinations inhibition of S6 phosphorylation was increased. The reduced synergy exhibited by NVP-BEZ235 in combination with MEK inhibitors, compared with GDC-0941, may be due to inhibition of mTOR, and the addition of the mTORC1/2 inhibitor KU0063794 compromised the synergy of GDC-0941:PD0325901 combinations. These studies confirm that dual targeting of PI3K and MEK can induce synergistic growth inhibition; however, the combination of specific PI3K inhibitors, rather than dual mTOR/PI3K inhibitors, with MEK inhibitors results in greater synergy.
    British Journal of Cancer 03/2012; 106(8):1386-94. · 5.08 Impact Factor
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    ABSTRACT: Structure-activity relationships for the MDM2-p53 inhibitory activity of a series of A-ring substituted 2-N-benzyl-3-(4-chlorophenyl)-3-(1-(hydroxymethyl)cyclopropyl)methoxy)isoindolinones have been investigated, giving rise to compounds with improved potency over their unsubstituted counterparts. Isoindolinone A-ring substitution with a 4-chloro group for the 4-nitrobenzyl, 4-bromobenzyl and 4-cyanobenzyl derivatives (10a-c) and substitution with a 6-tert-butyl group for the 4-nitrobenzyl derivative (10j) were found to confer additional potency. Resolution of the enantiomers of 10a showed that potent MDM2-p53 activity resided in the (-)-enantiomer ((-)-10a; IC(50)=44 ± 6 nM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compounds 10a and (-)-10a increase p53 protein levels, activate p53-dependent MDM2 and p21 transcription in MDM2 amplified cells, and show improved selectivity for growth inhibition in wild type p53 cell lines over the parent compound.
    Bioorganic & medicinal chemistry letters 08/2011; 21(19):5916-9. · 2.65 Impact Factor
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    ABSTRACT: We describe here the identification and characterization of 2 novel inhibitors of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases. The compounds exhibit selective inhibition of FGFR over the closely related VEGFR2 receptor in cell lines and in vivo. The pharmacologic profile of these inhibitors was defined using a panel of human tumor cell lines characterized for specific mutations, amplifications, or translocations known to activate one of the four FGFR receptor isoforms. This pharmacology defines a profile for inhibitors that are likely to be of use in clinical settings in disease types where FGFR is shown to play an important role.
    Molecular Cancer Therapeutics 07/2011; 10(9):1542-52. · 5.60 Impact Factor
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    ABSTRACT: Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclin-dependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA-wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers.
    Nature medicine 06/2011; 17(7):875-82. · 28.05 Impact Factor
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    ABSTRACT: Thiothymidine (S(4)TdR) can be incorporated into DNA and sensitise cells to DNA damage and cell death following exposure to UVA light. Studies were performed to determine if the combination of S(4)TdR and UVA could be an effective treatment for bladder cancer. Uptake and incorporation of S(4)TdR was determined in rat and human bladder tumour cell lines. Measures of DNA crosslinking and apoptosis were also performed. In vivo activity of the combination of S(4)TdR and UVA was investigated in an orthotopic model of bladder cancer in rats. Thiothymidine (200 μM) replaced up to 0.63% of thymidine in rat and tumour bladder cancer cells. The combination of S(4)TdR (10-200 μM) and UVA (1-5 kJ m(-2)) caused apoptosis and cell death at doses that were not toxic alone. Addition of raltitrexed (Astra Zeneca, Alderley Edge, Cheshire, UK) increased the incorporation of S(4)TdR into DNA (up to 20-fold at IC(5)) and further sensitised cells to UVA. Cytotoxic effect was associated with crosslinking of DNA, at least partially to protein. Intravenous administration of S(4)TdR, in combination with UVA delivered directly to the bladder, resulted in an antitumour effect in three of five animals treated. These data indicate that the combination of S(4)TdR and UVA has potential as a treatment for bladder cancer, and give some insight into the mechanism of action. Further work is necessary to optimise the delivery of the two components.
    British Journal of Cancer 06/2011; 104(12):1869-76. · 5.08 Impact Factor
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    ABSTRACT: Inhibition of DNA repair is emerging as a new therapeutic strategy for cancer treatment. One promising target is DNA-PK, a pivotal kinase in double-strand break repair. The purpose of this study was to further characterise the activity of the DNA-PK inhibitor NU7441, giving some new insights into the biology of DNA-PK. We used NU7441, a potent DNA-PK inhibitor, to evaluate potential pharmacodynamic markers of DNA-PK inhibition, inhibition of DNA repair and chemo- and radio-potentiation in isogenic human cancer cells proficient (M059-Fus1) and deficient (M059 J) in DNA-PK. NU7441 strongly inhibited DNA-PK in cell lines (IC(50) = 0.3 μM) but only weakly inhibited PI3 K (IC(50) = 7 μM). The only available anti-phospho-DNA-PK antibody also recognised some phosphoprotein targets of ATM. NU7441 caused doxorubicin- and IR-induced DNA DSBs (measured by γ-H2AX foci) to persist and also slightly decreased homologous recombination activity, as assessed by Rad51 foci. Chemo- and radio-potentiation were induced by NU7441 in M059-Fus-1, but not in DNA-PK-deficient M059 J cells. DNA-PK was highly expressed in a chronic lymphocytic leukaemia sample but undetectable in resting normal human lymphocytes, although it could be induced by PHA-P treatment. In K652 cells, DNA-PK expression was not related to cell cycle phase. These data confirm NU7441 not only as a potent chemo- and radio-sensitiser clinical candidate but also as a powerful tool to study the biology of DNA-PK.
    Cancer Chemotherapy and Pharmacology 06/2011; 69(1):155-64. · 2.80 Impact Factor
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    ABSTRACT: To facilitate the evaluation of CDK2 (cyclin-dependent kinase 2) as a cancer target, the in vitro and in vivo properties of NU6102 (O⁶-cyclohexylmethyl-2-(4'-sulphamoylanilino)purine) and a water soluble prodrug (NU6301) were investigated. NU6102 selectively inhibited the growth of CDK2 WT (wild type) versus KO MEFs (knockout mouse embryo fibroblasts) (GI₅₀ (concentration required to inhibit cell growth by 50%) 14 μM versus >30 μM), and was more growth-inhibitory in p53 mutant or null versus p53 WT cells (p=0.02), and in Rb (retinoblastoma protein) WT SKUT-1B versus SKUT 1 Rb deficient cells (p=0.01). In SKUT-1B cells NU6102 induced a G2 arrest, inhibition of Rb phosphorylation and cytotoxicity (LC₅₀ 2.6 μM for a 24h exposure). The prodrug NU6301 rapidly generated NU6102 in vitro in mouse plasma, and tumour NU6102 levels in vivo consistent with activity in vitro. Eight or 12 hourly dosing of 120 mg/kg NU6301 for 10 days was well tolerated in SKUT-1B tumour-bearing mice and inhibited Rb phosphorylation in tumour tissue. Two (8 hourly dosing) and 3 (12 hourly dosing) day tumour growth delay was observed (p=0.04 and p=0.007, respectively) following NU6301 administration. NU6102 and its prodrug NU6301 have pharmacological properties consistent with CDK2 inhibition, and represent useful tool molecules for the evaluation of CDK2 as a target in cancer.
    European journal of cancer (Oxford, England: 1990) 05/2011; 47(13):2052-9. · 4.12 Impact Factor
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    ABSTRACT: Two novel series of inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase (PARP) were synthesized and evaluated for biological activity. In the benzimidazole-4-carboxamide series, the carbamoyl function was restricted into the putative biologically active conformation via an intramolecular hydrogen bond, while for quinazolin-4-[3H]-ones this was achieved by incorporation of the group into a heterocyclic ring. For both series of compounds, syntheses involved acylation of substituted anthranilic acid derivatives, followed by acid- or base-catalysed cyclization. 8-Hydroxyquinazolin-4-[3H]-ones were prepared from the corresponding 8-methoxy compounds by dealkylation with boron tribromide.PARP inhibitory activity was determined in permeabilized L1210 murine leukaemia cells, in comparison with the established inhibitor 3-hydroxybenzamide (IC50 = 8-3 um). For both series, inhibitory activity varied with the nature of the 2-substituent, with benzimidazole-4-carboxamides proving approximately tenfold more potent than the previously prepared benzoxazole-4-carboxamides. 2-Arylbenzimidazoles were especially active, and 2-(4-methoxyphenyl)benzimidazole-4-carboxamide (IC50 = 60 nM) is the most potent PARP inhibitor reported to date. In the quinazolinone series, a 2-(4-nitrophenyl) substituent, and either an 8-methyl or 8-hydroxy group conferred potent inhibitory activity, with IC50 values of 0–13 and 0–23 μM, respectively, being observed.
    Pharmacy and Pharmacology Communications. 03/2011; 2(1):43 - 47.

Publication Stats

5k Citations
962.50 Total Impact Points

Institutions

  • 1992–2014
    • Newcastle University
      • • Northern Institute for Cancer Research
      • • School of Chemistry
      Newcastle-on-Tyne, England, United Kingdom
    • Wayne State University
      • Division of Hematology and Oncology
      Detroit, MI, United States
  • 2013
    • University of Newcastle
      Newcastle, New South Wales, Australia
  • 2003–2011
    • Northern Institute For Cancer Research
      Newcastle-on-Tyne, England, United Kingdom
    • Imperial College London
      Londinium, England, United Kingdom
  • 2005
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
      Milano, Lombardy, Italy
  • 2004
    • Wyeth
      New Johnsonville, Tennessee, United States
  • 2000–2003
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      Newcastle-on-Tyne, England, United Kingdom
  • 1999
    • United Arab Emirates University
      Al Ain, Abu Dhabi, United Arab Emirates
  • 1998
    • University of Leicester
      Leiscester, England, United Kingdom
  • 1985–1993
    • Institute of Cancer Research
      • Division of Cancer Therapeutics
      Londinium, England, United Kingdom