Enhancing Repair of Oxidative DNA Damage with Small-Molecule Activators of MTH1

Overview

Journal ACS Chem Biol

Publisher American Chemical Society

Specialties Biochemistry
Biology

Date 2022 Jul 13

PMID 35830623

Authors

Yujeong Lee

Yoshiyuki Onishi

Lisa McPherson

Anna M Kietrys

Marian Hebenbrock

Yong Woong Jun

Ishani Das

Shanthi Adimoolam

Debin Ji

Michael G Mohsen

James M Ford

Eric T Kool

Affiliations

Soon will be listed here.

Abstract

Impaired DNA repair activity has been shown to greatly increase rates of cancer clinically. It has been hypothesized that upregulating repair activity in susceptible individuals may be a useful strategy for inhibiting tumorigenesis. Here, we report that selected tyrosine kinase (TK) inhibitors including nilotinib, employed clinically in the treatment of chronic myeloid leukemia, are activators of the repair enzyme Human MutT Homolog 1 (MTH1). MTH1 cleanses the oxidatively damaged cellular nucleotide pool by hydrolyzing the oxidized nucleotide 8-oxo-2'-deoxyguanosine (8-oxo-dG)TP, which is a highly mutagenic lesion when incorporated into DNA. Structural optimization of analogues of TK inhibitors resulted in compounds such as SU0448, which induces 1000 ± 100% activation of MTH1 at 10 μM and 410 ± 60% at 5 μM. The compounds are found to increase the activity of the endogenous enzyme, and at least one (SU0448) decreases levels of 8-oxo-dG in cellular DNA. The results suggest the possibility of using MTH1 activators to decrease the frequency of mutagenic nucleotides entering DNA, which may be a promising strategy to suppress tumorigenesis in individuals with elevated cancer risks.

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References

Riley R, McGinnity D, Austin R . A unified model for predicting human hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and microsomes. Drug Metab Dispos. 2005; 33(9):1304-11. DOI: 10.1124/dmd.105.004259. View

Ossovskaya V, Koo I, Kaldjian E, Alvares C, Sherman B . Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types. Genes Cancer. 2011; 1(8):812-21. PMC: 3092251. DOI: 10.1177/1947601910383418. View

Donley N, Jaruga P, Coskun E, Dizdaroglu M, McCullough A, Lloyd R . Small Molecule Inhibitors of 8-Oxoguanine DNA Glycosylase-1 (OGG1). ACS Chem Biol. 2015; 10(10):2334-43. PMC: 4894821. DOI: 10.1021/acschembio.5b00452. View

Bhullar K, Lagaron N, McGowan E, Parmar I, Jha A, Hubbard B . Kinase-targeted cancer therapies: progress, challenges and future directions. Mol Cancer. 2018; 17(1):48. PMC: 5817855. DOI: 10.1186/s12943-018-0804-2. View

Cox P, Gregg R, Vasudevan A . Abbott Physicochemical Tiering (APT)--a unified approach to HTS triage. Bioorg Med Chem. 2012; 20(14):4564-73. DOI: 10.1016/j.bmc.2012.05.047. View

Markkanen E . Not breathing is not an option: How to deal with oxidative DNA damage. DNA Repair (Amst). 2017; 59:82-105. DOI: 10.1016/j.dnarep.2017.09.007. View

Russo M, Blasi M, Chiera F, Fortini P, Degan P, MacPherson P . The oxidized deoxynucleoside triphosphate pool is a significant contributor to genetic instability in mismatch repair-deficient cells. Mol Cell Biol. 2003; 24(1):465-74. PMC: 303369. DOI: 10.1128/MCB.24.1.465-474.2004. View

Irvine J, Takahashi L, Lockhart K, Cheong J, Tolan J, Selick H . MDCK (Madin-Darby canine kidney) cells: A tool for membrane permeability screening. J Pharm Sci. 1999; 88(1):28-33. DOI: 10.1021/js9803205. View

Boveris A, Valdez L, Zaobornyj T, Bustamante J . Mitochondrial metabolic states regulate nitric oxide and hydrogen peroxide diffusion to the cytosol. Biochim Biophys Acta. 2006; 1757(5-6):535-42. DOI: 10.1016/j.bbabio.2006.02.010. View

10.

Coles C, Condie A, Chetty U, Steel C, Evans H, Prosser J . p53 mutations in breast cancer. Cancer Res. 1992; 52(19):5291-8. View

11.

Rai P, Young J, Burton D, Giribaldi M, Onder T, Weinberg R . Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence. Oncogene. 2010; 30(12):1489-96. DOI: 10.1038/onc.2010.520. View

12.

Egashira A, Yamauchi K, Yoshiyama K, Kawate H, Katsuki M, Sekiguchi M . Mutational specificity of mice defective in the MTH1 and/or the MSH2 genes. DNA Repair (Amst). 2003; 1(11):881-93. DOI: 10.1016/s1568-7864(02)00113-1. View

13.

Osterod M, Hollenbach S, Hengstler J, Barnes D, Lindahl T, Epe B . Age-related and tissue-specific accumulation of oxidative DNA base damage in 7,8-dihydro-8-oxoguanine-DNA glycosylase (Ogg1) deficient mice. Carcinogenesis. 2001; 22(9):1459-63. DOI: 10.1093/carcin/22.9.1459. View

14.

Alli E, Ford J . BRCA1: a movement toward cancer prevention. Mol Cell Oncol. 2016; 2(3):e979685. PMC: 4905290. DOI: 10.4161/23723556.2014.979685. View

15.

Uitdehaag J, de Roos J, van Doornmalen A, Prinsen M, de Man J, Tanizawa Y . Comparison of the cancer gene targeting and biochemical selectivities of all targeted kinase inhibitors approved for clinical use. PLoS One. 2014; 9(3):e92146. PMC: 3961306. DOI: 10.1371/journal.pone.0092146. View

16.

van Loon B, Markkanen E, Hubscher U . Oxygen as a friend and enemy: How to combat the mutational potential of 8-oxo-guanine. DNA Repair (Amst). 2010; 9(6):604-16. DOI: 10.1016/j.dnarep.2010.03.004. View

17.

Guiard-Schmid J, Poirier J, Meynard J, Bonnard P, Gbadoe A, Amiel C . High variability of plasma drug concentrations in dual protease inhibitor regimens. Antimicrob Agents Chemother. 2003; 47(3):986-90. PMC: 149294. DOI: 10.1128/AAC.47.3.986-990.2003. View

18.

Wang S, Xie Y, Bao A, Li J, Ye T, Yang C . Nilotinib, a Discoidin domain receptor 1 (DDR1) inhibitor, induces apoptosis and inhibits migration in breast cancer. Neoplasma. 2021; 68(5):975-982. DOI: 10.4149/neo_2021_201126N1282. View

19.

Yuen G, Weller S, Pakes G . A review of the pharmacokinetics of abacavir. Clin Pharmacokinet. 2008; 47(6):351-71. DOI: 10.2165/00003088-200847060-00001. View

20.

Kim S, You D, Jeong Y, Yoon S, Kim S, Lee J . Inhibition of platelet-derived growth factor receptor synergistically increases the pharmacological effect of tamoxifen in estrogen receptor α positive breast cancer. Oncol Lett. 2021; 21(4):294. PMC: 7905523. DOI: 10.3892/ol.2021.12555. View