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Ann Oncol. 2016 Dec;27(12):2275-2283. doi: 10.1093/annonc/mdw429. Epub 2016 Nov 8.

Validation and development of MTH1 inhibitors for treatment of cancer.

Author information

1
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics.
2
Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology.
3
Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics.
4
Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
5
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
6
Sahlgrenska Translational Melanoma Group (SATMEG), Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg.
7
Department of Pharmacy and.
8
Science for Life Laboratory Drug Discovery and Development Platform, ADME of Therapeutics facility, Department of Phamracy, Uppsala University, Uppsala, Sweden.
9
Swedish Toxicology Sciences Research Center, Södertälje, Sweden.
10
National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm.
11
SP Process Development, Södertälje, Sweden.
12
Uppsala Drug Optimisation and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Uppsala University, Uppsala, Sweden.
13
Institute of biomedical sciences, Academia Sinica, Taipei-115, Taiwan.
14
Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
15
Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
16
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics thomas.helleday@scilifelab.se.

Abstract

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.

KEYWORDS:

DNA damage; MTH1; cancer; reactive oxygen species; small molecule inhibitors

PMID:
27827301
DOI:
10.1093/annonc/mdw429
[Indexed for MEDLINE]

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