Περίληψη:
Background: Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment. Material and methods: Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay. Thermal Proteome profiling, proteomics, cellular thermal shift assays, kinase and CEREP panel were used for target engagement, mode of action and selectivity investigations of MTH1 inhibitors. Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models. Results: Here, we demonstrate that recently described MTH1 inhibitors, which fail to kill cancer cells, also fail to introduce the toxic oxidized nucleotides into DNA. We also describe a new MTH1 inhibitor TH1579, (Karonudib), an analogue of TH588, which is a potent, selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo. Conclusion: We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
Συγγραφείς:
Berglund, U.W.
Sanjiv, K.
Gad, H.
Kalderén, C.
Koolmeister, T.
Pham, T.
Gokturk, C.
Jafari, R.
Maddalo, G.
Seashore-Ludlow, B.
Chernobrovkin, A.
Manoilov, A.
Pateras, I.S.
Rasti, A.
Jemth, A.-S.
Almlöf, I.
Loseva, O.
Visnes, T.
Einarsdottir, B.O.
Gaugaz, F.Z.
Saleh, A.
Platzack, B.
Wallner, O.A.
Vallin, K.
Henriksson, M.
Wakchaure, P.
Borhade, S.
Herr, P.
Kallberg, Y.
Baranczewski, P.
Homan, E.J.
Wiita, E.
Nagpal, V.
Meijer, T.
Schipper, N.
Rudd, S.G.
Bräutigam, L.
Lindqvist, A.
Filppula, A.
Lee, T.-C.
Artursson, P.
Nilsson, J.A.
Gorgoulis, V.G.
Lehtiö, J.
Zubarev, R.A.
Scobie, M.
Helleday, T.
Λέξεις-κλειδιά:
antineoplastic agent; B Raf kinase; cell protein; DNA; guanosine triphosphatase; protein 8 oxodG; protein MTH1; short hairpin RNA; small interfering RNA; th 1579; unclassified drug; 8-oxo-7-hydrodeoxyguanosine; 8-oxodGTPase; B Raf kinase; BRAF protein, human; deoxyguanosine; DNA; DNA ligase; enzyme inhibitor; nucleotide; phosphatase; pyrimidine derivative; small interfering RNA, animal cell; animal experiment; animal model; animal tissue; Article; cancer cell line; cancer chemotherapy; colon cancer; comet assay; controlled study; drug design; drug effect; drug exposure; drug mechanism; drug selectivity; female; gene mutation; HCT 116 cell line; human; human cell; immunohistochemistry; in vitro study; in vivo study; melanoma; mouse; nonhuman; priority journal; protein depletion; proteomics; SW480 cell line; tumor growth; tumor xenograft; analogs and derivatives; animal; antagonists and inhibitors; drug screening; genetics; isolation and purification; metabolism; neoplasm; oxidation reduction reaction; pathology; tumor cell line, Animals; Cell Line, Tumor; Deoxyguanosine; DNA; DNA Repair Enzymes; Enzyme Inhibitors; Humans; Mice; Neoplasms; Nucleotides; Oxidation-Reduction; Phosphoric Monoester Hydrolases; Proto-Oncogene Proteins B-raf; Pyrimidines; RNA, Small Interfering; Xenograft Model Antitumor Assays
