Search: onr:"swepub:oai:DiVA.org:uu-470347" >
Pharmacological tar...
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Bonagas, NadillyKarolinska Institutet
(author)
Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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2022-02-28
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Springer Science and Business Media LLC,2022
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-470347
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-470347URI
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https://doi.org/10.1038/s43018-022-00331-yDOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-310076URI
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https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-203237URI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:148956713URI
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https://lup.lub.lu.se/record/7e0eea0f-45be-41ba-8a0e-cc9ce8ca6504URI
Supplementary language notes
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Language:English
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Summary in:English
Part of subdatabase
Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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QC 20220321
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The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Gustafsson, Nina M. S.Karolinska Institutet
(author)
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Henriksson, MartinKarolinska Institutet
(author)
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Marttila, PetraKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Gustafsson, Robert,1988-Stockholms universitet,Institutionen för biokemi och biofysik,Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.(Swepub:su)rogu0454
(author)
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Wiita, EliseeKarolinska Institutet
(author)
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Borhade, SanjayKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Green, Alanna C.Univ Sheffield, Med Sch, Dept Oncol & Metab, Weston Pk Canc Ctr, Sheffield, S Yorkshire, England.
(author)
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Vallin, Karl S. A.Karolinska Institutet
(author)
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Sarno, AntonioKarolinska Institutet
(author)
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Svensson, RichardUppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab(Swepub:uu)ricsv977
(author)
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Gokturk, CamillaKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Pham, ThereseKarolinska Institutet
(author)
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Jemth, Ann-SofieKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Loseva, OlgaKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Cookson, VictoriaUniv Sheffield, Med Sch, Dept Oncol & Metab, Weston Pk Canc Ctr, Sheffield, S Yorkshire, England.
(author)
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Kiweler, NicoleLuxembourg Inst Hlth, Dept Oncol, Canc Metab Grp, Luxembourg, Luxembourg.
(author)
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Sandberg, LarsStockholms universitet,Science for Life Laboratory (SciLifeLab),Institutionen för organisk kemi,Stockholm Univ, Dept Organ Chem, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden.(Swepub:su)lasa3159
(author)
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Rasti, AzitaKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Unterlass, Judith E.Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Haraldsson, MartinKarolinska Institutet
(author)
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Andersson, YasminKTH,Läkemedelsutveckling,Science for Life Laboratory, SciLifeLab,Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden.(Swepub:kth)u1io9xl7
(author)
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Scaletti, Emma R.Stockholm University,Lunds universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Lund University, Sweden,Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.;Lund Univ, Dept Expt Med Sci, Lund, Sweden.,Strukturell biokemi,Forskargrupper vid Lunds universitet,Structural Biochemistry,Lund University Research Groups(Swepub:lu)em4772sc
(author)
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Bengtsson, ChristofferStockholms universitet,Science for Life Laboratory (SciLifeLab),Institutionen för organisk kemi,Stockholm Univ, Dept Organ Chem, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden.(Swepub:su)chben
(author)
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Jarvius, MalinUppsala universitet,Cancerfarmakologi och beräkningsmedicin,Science for Life Laboratory, SciLifeLab(Swepub:uu)maemi734
(author)
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Sanjiv, KumarKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Abdurakhmanov, Eldar,1977-Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab(Swepub:uu)eldab338
(author)
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Pudelko, LindaKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Kunz, BenKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Desroses, MatthieuKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Iliev, PetarKarolinska Institutet
(author)
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Färnegårdh, KatarinaStockholms universitet,Science for Life Laboratory (SciLifeLab),Institutionen för organisk kemi,Stockholm Univ, Dept Organ Chem, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden.(Swepub:su)kfr
(author)
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Kramer, AndreasGoethe Univ, Inst Pharmaceut Chem, Frankfurt, Germany.
(author)
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Garg, NeerajUppsala universitet,Science for Life Laboratory, SciLifeLab
(author)
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Michel, MauriceKarolinska Institutet
(author)
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Häggblad, SaraStockholms universitet,Science for Life Laboratory (SciLifeLab),Institutionen för biokemi och biofysik,Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, Solna, Sweden.(Swepub:su)sah
(author)
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Jarvius, MalinUppsala universitet,Cancerfarmakologi och beräkningsmedicin,Science for Life Laboratory, SciLifeLab(Swepub:uu)maemi734
(author)
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Kalderen, ChristinaKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Jensen, Amanda BogedahlKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Almlof, IngridKarolinska Institutet
(author)
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Karsten, StellaKarolinska Institutet
(author)
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Zhang, Si MinKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Häggblad, MariaStockholms universitet,Science for Life Laboratory (SciLifeLab),Institutionen för biokemi och biofysik,Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, Solna, Sweden.(Swepub:su)maha7002
(author)
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Eriksson, AndersKarolinska Inst, Karolinska High Throughput Ctr, Dept Biosci & Nutr, Huddinge, Sweden.
(author)
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Liu, JianpingKarolinska Inst, Karolinska High Throughput Ctr, Dept Biosci & Nutr, Huddinge, Sweden.
(author)
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Glinghammar, BjornKarolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden.
(author)
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Nekhotiaeva, NataliaKarolinska Inst, Karolinska High Throughput Ctr, Dept Biosci & Nutr, Huddinge, Sweden.
(author)
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Klingegård, FredrikStockholms universitet,Science for Life Laboratory (SciLifeLab),Institutionen för organisk kemi,Stockholm Univ, Dept Organ Chem, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden.(Swepub:su)fthor
(author)
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Koolmeister, TobiasKarolinska Institutet
(author)
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Martens, UlfStockholms universitet,Science for Life Laboratory (SciLifeLab),Institutionen för biokemi och biofysik,Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, Solna, Sweden.(Swepub:su)ulma3535
(author)
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Llona-Minguez, SabinKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Moulson, RuthKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Nordström, Helena,1974-Uppsala universitet,Biokemi(Swepub:uu)henor020
(author)
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Parrow, VendelaUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)venpa974
(author)
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Dahllund, LeifKTH,Läkemedelsutveckling,Science for Life Laboratory, SciLifeLab,Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden.(Swepub:kth)u1t0erdm
(author)
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Sjoberg, BirgerKarolinska Institutet
(author)
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Vargas, Irene L.Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Vo, Duy DucUppsala Univ, Dept Med Chem, Sci Life Lab, Uppsala, Sweden.
(author)
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Wannberg, JohanUppsala universitet,Science for Life Laboratory, SciLifeLab,Preparativ läkemedelskemi(Swepub:uu)jowan133
(author)
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Knapp, StefanGoethe Univ, Inst Pharmaceut Chem, Frankfurt, Germany.
(author)
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Krokan, Hans E.Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Trondheim, Norway.
(author)
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Arvidsson, Per, IKarolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden.
(author)
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Scobie, MartinKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(author)
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Meiser, JohannesLuxembourg Inst Hlth, Dept Oncol, Canc Metab Grp, Luxembourg, Luxembourg.
(author)
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Stenmark, PålStockholm University,Lunds universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Lund University, Sweden,Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.;Lund Univ, Dept Expt Med Sci, Lund, Sweden.,Strukturell biokemi,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Structural Biochemistry,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)pa4463st
(author)
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Berglund, Ulrika WarpmanKarolinska Institutet
(author)
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Homan, Evert J.Karolinska Institutet
(author)
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Helleday, ThomasKarolinska Institutet,University of Sheffield
(author)
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Karolinska InstitutetKarolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden.
(creator_code:org_t)
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et al.
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In:NATURE CANCER: Springer Science and Business Media LLC3:2, s. 156-2662-1347
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