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Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy (2014)

K. V. Huber ; E. Salah ; B. Radic ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 508(7495): 222-7. doi: 10.1038/nature13194.

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Publication Date: 2014-04-04

Description: Activated RAS GTPase signalling is a critical driver of oncogenic transformation and malignant disease. Cellular models of RAS-dependent cancers have been used to identify experimental small molecules, such as SCH51344, but their molecular mechanism of action remains generally unknown. Here, using a chemical proteomic approach, we identify the target of SCH51344 as the human mutT homologue MTH1 (also known as NUDT1), a nucleotide pool sanitizing enzyme. Loss-of-function of MTH1 impaired growth of KRAS tumour cells, whereas MTH1 overexpression mitigated sensitivity towards SCH51344. Searching for more drug-like inhibitors, we identified the kinase inhibitor crizotinib as a nanomolar suppressor of MTH1 activity. Surprisingly, the clinically used (R)-enantiomer of the drug was inactive, whereas the (S)-enantiomer selectively inhibited MTH1 catalytic activity. Enzymatic assays, chemical proteomic profiling, kinome-wide activity surveys and MTH1 co-crystal structures of both enantiomers provide a rationale for this remarkable stereospecificity. Disruption of nucleotide pool homeostasis via MTH1 inhibition by (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models. Our results propose (S)-crizotinib as an attractive chemical entity for further pre-clinical evaluation, and small-molecule inhibitors of MTH1 in general as a promising novel class of anticancer agents.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150021/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150021/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huber, Kilian V M -- Salah, Eidarus -- Radic, Branka -- Gridling, Manuela -- Elkins, Jonathan M -- Stukalov, Alexey -- Jemth, Ann-Sofie -- Gokturk, Camilla -- Sanjiv, Kumar -- Stromberg, Kia -- Pham, Therese -- Berglund, Ulrika Warpman -- Colinge, Jacques -- Bennett, Keiryn L -- Loizou, Joanna I -- Helleday, Thomas -- Knapp, Stefan -- Superti-Furga, Giulio -- 092809/Wellcome Trust/United Kingdom -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- F 4711/Austrian Science Fund FWF/Austria -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Apr 10;508(7495):222-7. doi: 10.1038/nature13194. Epub 2014 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. ; Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK. ; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17121 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695225" target="_blank"〉PubMed〈/a〉

Keywords: Aminoquinolines/pharmacology ; Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Colonic Neoplasms/drug therapy/genetics/pathology ; Crystallization ; DNA Breaks, Single-Stranded/drug effects ; DNA Repair ; DNA Repair Enzymes/*antagonists & inhibitors/biosynthesis/chemistry/*metabolism ; Disease Models, Animal ; Female ; Homeostasis/drug effects ; Humans ; Mice ; Mice, SCID ; Models, Molecular ; Nucleotides/metabolism ; Phosphoric Monoester Hydrolases/*antagonists & ; inhibitors/biosynthesis/chemistry/*metabolism ; Protein Conformation ; Protein Kinase Inhibitors/chemistry/*pharmacology ; Proteomics ; Proto-Oncogene Proteins/genetics ; Pyrazoles/chemistry/*pharmacology ; Pyridines/chemistry/*pharmacology ; Substrate Specificity ; Xenograft Model Antitumor Assays ; ras Proteins/genetics

Print ISSN: 0028-0836

Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics

Published by Nature Publishing Group (NPG)

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SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1 (2015)

M. Rebsamen ; L. Pochini ; T. Stasyk ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 519(7544): 477-81. doi: 10.1038/nature14107.

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Publication Date: 2015-01-07

Description: Cell growth and proliferation are tightly linked to nutrient availability. The mechanistic target of rapamycin complex 1 (mTORC1) integrates the presence of growth factors, energy levels, glucose and amino acids to modulate metabolic status and cellular responses. mTORC1 is activated at the surface of lysosomes by the RAG GTPases and the Ragulator complex through a not fully understood mechanism monitoring amino acid availability in the lysosomal lumen and involving the vacuolar H(+)-ATPase. Here we describe the uncharacterized human member 9 of the solute carrier family 38 (SLC38A9) as a lysosomal membrane-resident protein competent in amino acid transport. Extensive functional proteomic analysis established SLC38A9 as an integral part of the Ragulator-RAG GTPases machinery. Gain of SLC38A9 function rendered cells resistant to amino acid withdrawal, whereas loss of SLC38A9 expression impaired amino-acid-induced mTORC1 activation. Thus SLC38A9 is a physical and functional component of the amino acid sensing machinery that controls the activation of mTOR.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376665/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376665/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rebsamen, Manuele -- Pochini, Lorena -- Stasyk, Taras -- de Araujo, Mariana E G -- Galluccio, Michele -- Kandasamy, Richard K -- Snijder, Berend -- Fauster, Astrid -- Rudashevskaya, Elena L -- Bruckner, Manuela -- Scorzoni, Stefania -- Filipek, Przemyslaw A -- Huber, Kilian V M -- Bigenzahn, Johannes W -- Heinz, Leonhard X -- Kraft, Claudine -- Bennett, Keiryn L -- Indiveri, Cesare -- Huber, Lukas A -- Superti-Furga, Giulio -- P 26682/Austrian Science Fund FWF/Austria -- England -- Nature. 2015 Mar 26;519(7544):477-81. doi: 10.1038/nature14107. Epub 2015 Jan 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. ; Department DiBEST (Biology, Ecology and Earth Sciences), University of Calabria, 87036 Arcavacata di Rende, Italy. ; Biocenter, Division of Cell Biology, Innsbruck Medical University, 6020 Innsbruck, Austria. ; Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25561175" target="_blank"〉PubMed〈/a〉

Keywords: Amino Acid Transport Systems/*metabolism ; Amino Acids/*metabolism ; Animals ; Cell Line ; Humans ; Lysosomes/*metabolism ; Mice ; Monomeric GTP-Binding Proteins/metabolism ; Multiprotein Complexes/*metabolism ; Nucleotides/metabolism ; TOR Serine-Threonine Kinases/*metabolism

Print ISSN: 0028-0836

Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics