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TAROX SIGNED

Targeting oxidative repair proteins for treatment of cancer and inflammation

Total Cost €

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EC-Contrib. €

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Partnership

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Project "TAROX" data sheet

The following table provides information about the project.

Coordinator
KAROLINSKA INSTITUTET 

Organization address
address: Nobels Vag 5
city: STOCKHOLM
postcode: 17177
website: www.ki.se

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Sweden [SE]
 Total cost 2˙279˙406 €
 EC max contribution 2˙279˙406 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2015-AdG
 Funding Scheme ERC-ADG
 Starting year 2016
 Duration (year-month-day) from 2016-08-01   to  2021-07-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    KAROLINSKA INSTITUTET SE (STOCKHOLM) coordinator 2˙279˙406.00

Map

 Project objective

Oxidative damage and defects in DNA repair are frequently underlying many diseases, e.g., cancer, autoimmune diseases, ischemia/reperfusion injury, neurodegenerative disorders, viral diseases and ageing. Although some molecular understanding into oxidative DNA lesions and repair proteins exist, a thorough understanding on the link to diseases is largely missing, and therapies exploiting oxidative DNA damage and repair have not emerged. Here, we will study mechanisms of nucleotide metabolism and oxidative DNA damage and repair, and generate tools and make use of ‘omics’ approaches to explore the function of the Nudix and glycosylases family enzymes in relation to oxidative metabolism. Furthermore, we will progress and understand the basic mechanisms how oxidative DNA lesions are processed and kill cells. Importantly, we will develop small molecule inhibitors targeting Nudix and glycosylases, e.g. MTH1, NUDT15 and OGG1, and use our newly developed inhibitors to increase our knowledge of these enzymes in oxidative metabolism and disease. We will further optimize these inhibitors into drugs and explore therapeutic approaches in cancer and inflammation as well as in exploratory studies in a variety of diseases involving oxidative stress. Altogether, in this programme we contribute to deepen our knowledge into the fundamental biology of oxidative stress and its links with disease, and providing the scientific community with an innovative repertoire of selective inhibitors for numerous enzymes involved in repair of oxidative lesions. This will enable exploratory basic science discoveries as well as potential novel therapeutic interventions ‘outside the box’. The programme will also generate high value to the industrial competitiveness of Europe in form of novel inhibitors for treatment of diseases.

 Publications

year authors and title journal last update
List of publications.
2018 Alice Lallo, Sakshi Gulati, Maximilian W Schenk, Garima Khandelwal, Ulrika Warpman Berglund, Ioannis S Pateras, Christopher P E Chester, Therese M Pham, Christina Kalderen, Kristopher K Frese, Vassilis G Gorgoulis, Crispin Miller, Fiona Blackhall, Thomas Helleday, Caroline Dive
Ex vivo culture of cells derived from circulating tumour cell xenograft to support small cell lung cancer research and experimental therapeutics
published pages: , ISSN: 0007-1188, DOI: 10.1111/bph.14542
British Journal of Pharmacology 2019-04-12
2019 Sean G Rudd, Helge Gad, Nuno Amaral, Anna Hagenkort, Petra Groth, Cecilia E Ström, OliverMortusewicz, Ulrika Warpman Berglund, Thomas Helleday
MTH1 inhibitor TH588 induces mitosis-dependent accumulation of genomic 8-oxodG and disturbs mitotic progression
published pages: , ISSN: , DOI: 10.1101/573931
bioRxiv 2019-04-12
2018 Torkild Visnes, Armando Cázares-Körner, Wenjing Hao, Olov Wallner, Geoffrey Masuyer, Olga Loseva, Oliver Mortusewicz, Elisée Wiita, Antonio Sarno, Aleksandr Manoilov, Juan Astorga-Wells, Ann-Sofie Jemth, Lang Pan, Kumar Sanjiv, Stella Karsten, Camilla Gokturk, Maurice Grube, Evert J. Homan, Bishoy M. F. Hanna, Cynthia B. J. Paulin, Therese Pham, Azita Rasti, Ulrika Warpman Berglund, Catharina von Nicolai, Carlos Benitez-Buelga, Tobias Koolmeister, Dag Ivanic, Petar Iliev, Martin Scobie, Hans E. Krokan, Pawel Baranczewski, Per Artursson, Mikael Altun, Annika Jenmalm Jensen, Christina Kalderén, Xueqing Ba, Roman A. Zubarev, Pål Stenmark, Istvan Boldogh, Thomas Helleday
Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation
published pages: 834-839, ISSN: 0036-8075, DOI: 10.1126/science.aar8048
Science 362/6416 2019-04-12
2018 Ann-Sofie Jemth, Emma Scaletti, Megan Carter, Thomas Helleday, PÃ¥l Stenmark
Crystal Structure and Substrate Specificity of the 8-oxo-dGTP Hydrolase NUDT1 from Arabidopsis thaliana
published pages: 887-899, ISSN: 0006-2960, DOI: 10.1021/acs.biochem.8b00950
Biochemistry 58/7 2019-04-12
2019 Helge Gad, Oliver Mortusewicz, Sean G Rudd, Ailine Stolz, Nuno Amaral, Lars Brautigham, Linda Pudelko, Kumar Sanjiv, Christina Kaldéren, Ann-Sofie Jemth, Ingrid Almlöf, Torkild Visnes, Niklas Schultz, JohanBoström, José Manuel Calderon Montano, Anna Hagenkort, Petra Groth, Olga Loseva, Camilla Gokturk, Tobias Koolmeister, Prasad Wakchaure, Evert Homan, Cecilia E Ström, Martin Scobie, Holger Bastians, Ulrika Warpman Berglund, Thomas Helleday
MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells
published pages: , ISSN: , DOI: 10.1101/575290
2019-04-12
2016 Nicholas C.K. Valerie, Anna Hagenkort, Brent D.G. Page, Geoffrey Masuyer, Daniel Rehling, Megan Carter, Luka Bevc, Patrick Herr, Evert Homan, Nina G. Sheppard, PÃ¥l Stenmark, Ann-Sofie Jemth, Thomas Helleday
NUDT15 Hydrolyzes 6-Thio-DeoxyGTP to Mediate the Anticancer Efficacy of 6-Thioguanine
published pages: 5501-5511, ISSN: 0008-5472, DOI: 10.1158/0008-5472.can-16-0584
Cancer Research 76/18 2019-04-12
2018 Mohit Narwal, Ann-Sofie Jemth, Robert Gustafsson, Ingrid Almlöf, Ulrika Warpman Berglund, Thomas Helleday, Pål Stenmark
Crystal Structures and Inhibitor Interactions of Mouse and Dog MTH1 Reveal Species-Specific Differences in Affinity
published pages: 593-603, ISSN: 0006-2960, DOI: 10.1021/acs.biochem.7b01163
Biochemistry 57/5 2019-04-12
2018 Ann-Sofie Jemth, Robert Gustafsson, Lars Bräutigam, Linda Henriksson, Karl S A Vallin, Antonio Sarno, Ingrid Almlöf, Evert Homan, Azita Rasti, Ulrika Warpman Berglund, Pål Stenmark, Thomas Helleday
MutT homologue 1 (MTH1) catalyzes the hydrolysis of mutagenic O6-methyl-dGTP
published pages: , ISSN: 0305-1048, DOI: 10.1093/nar/gky896
Nucleic Acids Research 2019-04-12
2018 \"Carter M, Jemth AS, Carreras-Puigvert J, Herr P, Martínez Carranza M, Vallin KSA, Throup A, Helleday T#, Stenmark P#.\"
Human NUDT22 Is a UDP-Glucose/Galactose Hydrolase Exhibiting a Unique Structural Fold. Structure. Feb 6;26(2):295-303.e6.
published pages: 295-303.e6, ISSN: 2352-0124, DOI: 10.1016/j.str.2018.01.004
Structure 26/2 2019-04-12
2018 Brent D. G. Page, Nicholas C. K. Valerie, Roni H. G. Wright, Olov Wallner, Rebecka Isaksson, Megan Carter, Sean G. Rudd, Olga Loseva, Ann-Sofie Jemth, Ingrid Almlöf, Jofre Font-Mateu, Sabin Llona-Minguez, Pawel Baranczewski, Fredrik Jeppsson, Evert Homan, Helena Almqvist, Hanna Axelsson, Shruti Regmi, Anna-Lena Gustavsson, Thomas Lundbäck, Martin Scobie, Kia Strömberg, Pål Stenmark, Miguel Beato, Thomas Helleday
Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells
published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-017-02293-7
Nature Communications 9/1 2019-04-12
2017 Jordi Carreras-Puigvert, Marinka Zitnik, Ann-Sofie Jemth, Megan Carter, Judith E. Unterlass, Björn Hallström, Olga Loseva, Zhir Karem, José Manuel Calderón-Montaño, Cecilia Lindskog, Per-Henrik Edqvist, Damian J. Matuszewski, Hammou Ait Blal, Ronnie P. A. Berntsson, Maria Häggblad, Ulf Martens, Matthew Studham, Bo Lundgren, Carolina Wählby, Erik L. L. Sonnhammer, Emma Lundberg, Pål Stenmark, Blaz Zupan, Thomas Helleday
A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family
published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-017-01642-w
Nature Communications 8/1 2019-04-12
2018 Sofia Henriksson, Petra Groth, Nina Gustafsson, Thomas Helleday
Distinct mechanistic responses to replication fork stalling induced by either nucleotide or protein deprivation
published pages: 568-579, ISSN: 1538-4101, DOI: 10.1080/15384101.2017.1387696
Cell Cycle 17/5 2019-04-12
2017 Axel Rudling, Robert Gustafsson, Ingrid Almlöf, Evert Homan, Martin Scobie, Ulrika Warpman Berglund, Thomas Helleday, Pål Stenmark, Jens Carlsson
Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space
published pages: 8160-8169, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b01006
Journal of Medicinal Chemistry 60/19 2019-04-12
2017 Linda Pudelko, Pegah Rouhi, Kumar Sanjiv, Helge Gad, Christina Kalderén, Andreas Höglund, Massimo Squatrito, Alberto J. Schuhmacher, Steven Edwards, Daniel Hägerstrand, Ulrika Warpman Berglund, Thomas Helleday, Lars Bräutigam
Glioblastoma and glioblastoma stem cells are dependent on functional MTH1
published pages: , ISSN: 1949-2553, DOI: 10.18632/oncotarget.19404
Oncotarget 8/49 2019-04-12

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