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Validation and development of MTH1 inhibitors for treatment of cancer
Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden..
Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden..
Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden..
Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden..
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2016 (English)In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 27, no 12, p. 2275-2283Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 27, no 12, p. 2275-2283
Keywords [en]
MTH1, reactive oxygen species, cancer, small molecule inhibitors, DNA damage
National Category
Cancer and Oncology Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-316436DOI: 10.1093/annonc/mdw429ISI: 000392825100021OAI: oai:DiVA.org:uu-316436DiVA, id: diva2:1077890
Funder
Knut and Alice Wallenberg Foundation, KAW 2014.0273 KAW 2014-0080Swedish Foundation for Strategic Research , RB13-0224 RIF14-0046Swedish Cancer Society, 2013-3791 CAN 2012/770Swedish Childhood Cancer Foundation, PR2014-0048 PR2013-0002 PR2014-0155 TJ2016-0035 SSF/01-05VINNOVA, 2014-03480Helge Ax:son Johnsons stiftelse EU, European Research Council, 268815 62029Torsten Söderbergs stiftelseRagnar Söderbergs stiftelseStockholm County CouncilAvailable from: 2017-03-01 Created: 2017-03-01 Last updated: 2018-01-13Bibliographically approved

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Gaugaz, Fabienne Z.Saleh, AljonaBaranczewski, PawelLindqvist, AnnikaFilppula, AnneArtursson, Per
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Department of PharmacyScience for Life Laboratory, SciLifeLab
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