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  • 1. Gad, Helge
    et al.
    Svensson, Linda M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Saleh, Aljona
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Berntsson, Ronnie P.-A.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gustafsson, Robert
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Johansson, Fredrik
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Djureinovic, Tatjana
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Häggblad, Maria
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Martens, Ulf
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lundgren, Bo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Granelli, Ingrid
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Helleday, Thomas
    MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 508, no 7495, p. 215-221Article in journal (Refereed)
    Abstract [en]

    Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

  • 2. Jayamanne, M
    et al.
    Granelli, I
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Tjernberg, A
    Edlund, P-O
    Development of a two-dimensional liquid chromatography system for isolation of drug metabolites2010In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 51, no 3, p. 649-657Article in journal (Refereed)
    Abstract [en]

    The separation, isolation and identification of drug metabolites from complex endogenous matrices like urine, plasma and tissue extracts are challenging tasks. Metabolites are usually first identified by mass spectrometry and tentative structures proposed from product ion spectra. In many cases mass spectrometry cannot be used to determine positional isomers and metabolites have to be fractionated in microgram amounts for analysis by NMR. To overcome the difficulties associated with separation and isolation of drug metabolites from biological matrices, a new two-dimensional liquid chromatography system has been developed. The retention times of 45 acidic, basic and neutral compounds were determined on liquid chromatographic columns with different stationary phases in order to identify two columns with highly different selectivity to be used for two-dimensional liquid chromatography. Drug metabolites of three model compounds were first generated in vitro with liver microsomes and then compared with potential metabolites formed by oxidation with hydrogen peroxide catalyzed by meso-tetra (4-sulphonatophenyl) porphine (porphine). The results showed that the porphine system could be used as a complementary system for the generation of phase I microsomal metabolites with high yield of some metabolites in a less complex matrix. The two-dimensional liquid chromatography system was used to separate and isolate microsomal and porphine generated drug metabolites in off-line and on-line mode. Finally, to verify the utility of the developed system, urine samples were spiked with metabolite standards of model compounds for separation in the two-dimensional system. Excellent separations were obtained with an amide column in the first dimension and a pentafluorophenylpropyl (PFPP) column in the second dimension. The metabolites were successfully separated from each other as well as from the complex biological matrix. The results demonstrate the applicability of the system for fractionation of drug metabolites but it could also be used in many other analytical purposes, especially for basic compounds. Trace levels of metabolites were successfully separated in the on-line mode which failed in the off-line mode.

     

     

     

  • 3.
    Saleh, Aljona
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Bruno, Oscar
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Granelli, Ingrid
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Edlund, Per-Olof
    Digestion of Enolase and Carbonic Anhydrase as Model Proteins for Therapeutic Proteins in Blood Plasma with Immobilized Thermolysin and Quantification of Some of the Peptides by LC/LC-MS/MS2014In: Chromatographia, ISSN 0009-5893, E-ISSN 1612-1112, Vol. 77, no 1-2, p. 59-74Article in journal (Refereed)
    Abstract [en]

    There is a need for fast method development in the early drug discovery phase of therapeutic proteins. Thermolysin has not been used for quantification of proteins in blood plasma earlier. It is a thermostable protease which permits the use of high temperatures for fast hydrolysis of proteins. Model proteins were digested with immobilized thermolysin on agarose gel. Protein-specific peptides were selected for quantitation and quantified based on stable isotope dilution. Protein digests of blood plasma were cleaned and separated using an automated LC/LC-MS/MS system. Essential digestion parameters that influence thermolysin hydrolytic activity were optimized for high peptide yield. The validated methods were selective, linear, precise and accurate with a limit of detection of 2 nM for both proteins. The proposed strategy for method development could be valuable for quantification of proteins in blood plasma samples. The study underscores and discusses important features of the enzymatic digestion and chromatographic separation.

  • 4.
    Saleh, Aljona
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Gokturk, Camilla
    Warpman-Berglund, Ulrika
    Helleday, Thomas
    Granelli, Ingrid
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Development and validation of method for TH588 and TH287, potent MTH1 inhibitors and new anti-cancer agents, for pharmacokinetic studies in mice plasma2015In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 104, p. 1-11Article in journal (Refereed)
    Abstract [en]

    MTH1 is a protein that is required for cancer cell survival and is overexpressed in cancer cells. TH588 and TH287 are two new compounds that inhibit the MTH1 protein. The inhibitors were tested in pharmacokinetic studies on mice. A bioanalytical method was developed and validated for determination in mice plasma. The method was based on protein precipitation followed by LC-MS/MS analysis. The separation was performed on an Ascentis Express RP-Amide C-18 column. The mass spectrometer was operated in positive electrospray ionization mode and the analytes were determined with multiple reaction monitoring (MRM). Abundant monoisotopic fragments were used for quantification. Two additional fragments were used for conformational analysis. The recovery of the compounds in plasma varied between 61 and 91% and the matrix effects were low and ranged between -3% and +2%. The method showed to be selective, linear, accurate and precise, and applicable for preclinical pharmacokinetic studies of TH588 and TH287 in mouse plasma. Half-life (T-1/2) was <= 3.5 h and maximum concentration (C-max) ranged between 0.82 and 338 mu M for the different administration routes and compounds.

  • 5.
    Saleh, Aljona
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Stephanson, Niclas Nicolai
    Granelli, Ingrid
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Villen, Tomas
    Beck, Olof
    Evaluation of a direct high-capacity target screening approach for urine drug testing using liquid chromatography-time-of-flight mass spectrometry2012In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, no 909, p. 6-13Article in journal (Refereed)
    Abstract [en]

    In this study a rapid liquid chromatography-time-of-flight mass spectrometry method was developed, validated and applied in order to evaluate the potential of this technique for routine urine drug testing. Approximately 800 authentic patient samples were analyzed for amphetamines (amphetamine and methamphetamine), opiates (morphine, morphine-3-glucuronide, morphine-6-glucuronide, codeine and codeine-6-glucuronide) and buprenorphines (buprenorphine and buprenorphine-glucuronide) using immunochemical screening assays and mass spectrometry confirmation methods for comparison. The chromatographic application utilized a rapid gradient with high flow and a reversed phase column with 1.8 mu m particles. Total analysis time was 4 min. The mass spectrometer operated with an electrospray interface in positive mode with a resolution power of >10,000 at m/z 956. The applied reporting limits were 100 ng/mL for amphetamines and opiates, and 5 ng/mL for buprenorphines, with lower limits of quantification were 2.8-41 ng/mL. Calibration curves showed a linear response with coefficients of correlation of 0.97-0.99. The intra- and interday imprecision in quantification at the reporting limits were <10% for all analytes but for buprenorphines <20%. Method validation data met performance criteria for a qualitative and quantitative method. The liquid chromatography-time-of-flight mass spectrometry method was found to be more selective than the immunochemical method by producing lower rates of false positives (0% for amphetamines and opiates; 3.2% for buprenorphines) and negatives (1.8% for amphetamines; 0.6% for opiates; 0% for buprenorphines). The overall agreement between the two screening methods was between 94.2 and 97.4%. Comparison of data with the confirmation (LC-MS) results for all individual 9 analytes showed that most deviating results were produced in samples with low levels of analytes. False negatives were mainly related to failure of detected peak to meet mass accuracy criteria (+/- 20 mDa). False positives was related to presence of interfering peaks meeting mass accuracy and retention time criteria and occurred mainly at low levels. It is concluded that liquid chromatography-time-of-flight mass spectrometry has potential both as a complement and as replacement of immunochemical screening assays.

  • 6. Sroka-Markovic, Janina
    et al.
    Johansson, Linda
    Andersson, Magnus B. O.
    Granelli, Ingrid
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Development of an HPLC Method for Determination of Related Impurities in Prilocaine Substance2012In: Chromatographia, ISSN 0009-5893, E-ISSN 1612-1112, Vol. 75, no 7-8, p. 329-336Article in journal (Refereed)
    Abstract [en]

    Development of a reversed phase high performance liquid chromatographic method for determination of six related impurities in prilocaine substance is reported. The test of related impurities in European Pharmacopoeia (Ph. Eur.) cannot meet the demands with the chromatographic parameters given, therefore different types of chromatographic systems and eight columns have been evaluated in the present study. A new method with a Hypercarb column was developed and validated. This method fulfils the demands in the Ph. Eur., and the validation shows that the method is selective, reproducible, linear, accurate and robust with sufficient limits of detection (0.001-0.004% of 2.5 mg prilocaine mL(-1)) and quantification (0.002-0.009% of 2.5 mg prilocaine mL(-1)).

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