The MTH1 inhibitor TH588 is a microtubule-modulating agent that eliminates cancer cells by activating the mitotic surveillance pathway

Gul, Nadia; Karlsson, Jan Ch; Tängemo, Carolina; Linsefors, Sanna; Tuyizere, Samuel; Perkins, Rosie; Ala, Chandu; Zou, Zhiyuan; Larsson, Erik; Bergö, Martin O.; Lindahl, Per

doi:10.1038/s41598-019-51205-w

Cited by 27 publications

(31 citation statements)

References 38 publications

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“…Kawamura et al. 26 , 31 , 47 , 48 have suggested that TH287 and TH588 might display their antitumor activities through off-target effect by suppressing tubulin polymerization, whereas these inhibitors were subsequently proved to activate in a different manner as compared to anti-microtubule agent. Indeed, it was recently demonstrated that MTH1 could bind tubulin and promote the progression of mitosis in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

Yin

Chen

2020

Acta Pharmaceutica Sinica B

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Since accelerated metabolism produces much higher levels of reactive oxygen species (ROS) in cancer cells compared to ROS levels found in normal cells, human MutT homolog 1 (MTH1), which sanitizes oxidized nucleotide pools, was recently demonstrated to be crucial for the survival of cancer cells, but not required for the proliferation of normal cells. Therefore, dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells. While several inhibitors were indeed confirmed to be effective, some inhibitors failed to kill cancer cells, complicating MTH1 as a viable target for cancer eradication. In this review, we summarize the current status of developing MTH1 inhibitors as drug candidates, classify the MTH1 inhibitors based on their structures, and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1.

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Section: Discussionmentioning

confidence: 99%

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

Yin

Chen

2020

Acta Pharmaceutica Sinica B

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“…S3). To uncover quantitative differences in the DNA damage response, we established dose-response curves for cisplatin and etoposide that activates p53 through ATM/ATR, and for TH588 that activates p53 though USP28 24 . There was no difference in IC50 values between ZNF148 knockout cells and controls in any of the tested cell lines (Fig.…”

Section: Zfp148 Binds To Clustered Cytosine-rich Dna Elements In Basamentioning

confidence: 99%

Genomic profiling of the transcription factor Zfp148 and its impact on the p53 pathway

Zou

Gul

Lindberg

et al. 2020

Sci Rep

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Recent data suggest that the transcription factor Zfp148 represses activation of the tumor suppressor p53 in mice and that therapeutic targeting of the human orthologue ZNF148 could activate the p53 pathway without causing detrimental side effects. We have previously shown that Zfp148 deficiency promotes p53-dependent proliferation arrest of mouse embryonic fibroblasts (MEFs), but the underlying mechanism is not clear. Here, we showed that Zfp148 deficiency downregulated cell cycle genes in MEFs in a p53-dependent manner. Proliferation arrest of Zfp148-deficient cells required increased expression of ARF, a potent activator of the p53 pathway. Chromatin immunoprecipitation showed that Zfp148 bound to the ARF promoter, suggesting that Zfp148 represses ARF transcription. However, Zfp148 preferentially bound to promoters of other transcription factors, indicating that deletion of Zfp148 may have pleiotropic effects that activate ARF and p53 indirectly. In line with this, we found no evidence of genetic interaction between TP53 and ZNF148 in cRiSpR and siRnA screen data from hundreds of human cancer cell lines. We conclude that Zfp148 deficiency, by increasing ARF transcription, downregulates cell cycle genes and cell proliferation in a p53-dependent manner. However, the lack of genetic interaction between ZNF148 and TP53 in human cancer cells suggests that therapeutic targeting of ZNF148 may not increase p53 activity in humans. Activation of the tumor suppressor p53 may have beneficial effects on tumors with wild-type p53 1. The first drugs targeting the p53 repressor murine double minute 2 (MDM2) have entered clinical trials, but their clinical benefit is still under evaluation 2. Because knockout of Mdm2 in mice causes widespread and lethal activation of p53 in normal tissues 3 , efficient pharmacological inhibition of MDM2 may have adverse effects. Thus, identifying alternative ways to activate the p53 pathway with less adverse effects is warranted. Zinc finger protein 148 (Zfp148, Zbp-89, BFCOL, BERF1, htβ) is a transcription factor that binds to GC-rich DNA sequences, thus activating or repressing transcription of target genes 4-11. Earlier studies have shown that Zfp148 is a potent repressor of p53 activity in mice. Firstly, deletion of Zfp148 caused p53-dependent proliferation arrest of cultured mouse embryonic fibroblasts (MEFs) and prenatal lung tissue that was rescued by reducing oxidative stress 12. Moreover, deletion of one copy of Zfp148 in the Apc Min/+ model of intestinal adenomas reduced tumor numbers and increased survival by increasing p53 activity 13. In line with this, conditional deletion of one or both alleles of Zfp148 in the gut epithelium of Apc FL/+ mice reduced tumor formation through a mechanism

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“…On top of the MTH1 inhibition, alternative mechanisms of TH588 have been reported as its anti-cancer effects including tubulin depolymerization and AKT signaling downregulation [ 32 , 33 ]. To confirm it, we investigated the spindle morphology of mitotic cells upon treatment of 5 and 10 µM of TH588.…”

Section: Resultsmentioning

confidence: 99%

A high-throughput drug combination screen identifies an anti-glioma synergism between TH588 and PI3K inhibitors

Chen

Zhou

et al. 2020

Cancer Cell Int

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Background: Glioblastoma multiforme (GBM) is the most common and lethal type of primary brain tumor. More than half of GBMs contain mutation(s) of PTEN/PI3K/AKT, making inhibitors targeting the PI3K pathway very attractive for clinical investigation. However, so far, PI3K/AKT/mTOR inhibitors have not achieved satisfactory therapeutic effects in clinical trials of GBM. In this study, we aimed to develop a high-throughput screening method for high-throughput identification of potential targeted agents that synergize with PI3K inhibitors in GBM. Methods: A Sensitivity Index (SI)-based drug combination screening method was established to evaluate the interactions between BKM120, a pan-PI3K inhibitor, and compounds from a library of 606 target-selective inhibitors. Proliferation, colony and 3D spheroid formation assays, western blotting, comet assay, γ-H2AX staining were used to evaluate the anti-glioma effects of the top-ranked candidates. The drug combination effects were analyzed by the Chou-Talalay method. Results: Six compounds were successfully identified from the drug screen, including three previously reported compounds that cause synergistic antitumor effects with PI3K/mTOR inhibitors. TH588, an putative MTH1 inhibitor exhibited significant synergy with BKM120 in suppressing the proliferation, colony formation and 3D spheroid formation of GBM cells. Further investigation revealed that both DNA damage and apoptosis were markedly enhanced upon combination treatment with TH588 and BKM120. Finally, activation of PI3K or overexpression of AKT compromised the anti-glioma efficacy of TH588. Conclusions: The screening method developed in this study demonstrated its usefulness in the rapid identification of synergistic drug combinations of PI3K inhibitors and targeted agents.

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The MTH1 inhibitor TH588 is a microtubule-modulating agent that eliminates cancer cells by activating the mitotic surveillance pathway

Cited by 27 publications

References 38 publications

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

Genomic profiling of the transcription factor Zfp148 and its impact on the p53 pathway

A high-throughput drug combination screen identifies an anti-glioma synergism between TH588 and PI3K inhibitors

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