Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target

Ellermann, Manuel; Eheim, Ashley; Rahm, Fredrik; Viklund, Jenny; Guenther, Judith; Andersson, Martin; Ericsson, U.B.; Forsblom, Rickard; Ginman, Tobias; Lindström, Johan; Silvander, C.; Tresaugues, L.; Giese, Anja; Bunse, Stefanie; Neuhaus, Roland; Weiske, Jörg; Quanz, Maria; Glasauer, Andrea; Nowak-Reppel, Katrin; Bader, Benjamin; Irlbacher, Horst; Meyer, Hanna; Queisser, Nina; Bauser, Marcus; Haegebarth, Andrea; Gorjánácz, Mátyás

doi:10.1021/acschembio.7b00370

Cited by 50 publications

(82 citation statements)

References 16 publications

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“…Recent reports indicated that cancer cells were also heavily dependent on functional MTH1 to maintain stemness and tumorigenesis [37,38]. Several small molecular inhibitor of MTH1 including TH588, BAY707 and S-crizotinib were developed and their anti-tumor activities looks promising [27,39,40]. For TH588, some researchers questioned its target speci city as this agent also possesses microtubule-modulating activity.…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Zhou

et al. 2020

Preprint

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Abstract 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, a 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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Section: Discussionmentioning

confidence: 99%

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

Chen

Zhou

et al. 2020

Preprint

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“…While the underlying biology behind MTH1's involvement in tolerance to oncogene-induced oxidative stress is emerging [87,[105][106][107][108][109][110][111], the biology of small molecule MTH1 inhibitors remains unresolved in the literature. Several MTH1 inhibitor series fail to kill cancer cells, despite apparent successful target engagement in cells [112][113][114][115]. A key observation is that the anti-cancer effect seems to be coupled to accumulation of oxidized bases in the genome, as the MTH1 inhibitors that fail to accumulate oxidized bases also fail to kill cancer cells [96,115].…”

Section: Sensitization To Endogenous Cancer-specific Dna Damagementioning

confidence: 99%

“…Several MTH1 inhibitor series fail to kill cancer cells, despite apparent successful target engagement in cells [112][113][114][115]. A key observation is that the anti-cancer effect seems to be coupled to accumulation of oxidized bases in the genome, as the MTH1 inhibitors that fail to accumulate oxidized bases also fail to kill cancer cells [96,115]. Since these oxidized bases are substrates for BER, it follows that inhibitors to BER could be used to either potentiate the effect of MTH1 inhibitors, or to kill subsets of cancers where the cancer cell relies more on downstream BER than MTH1 to maintain viability.…”

Section: Sensitization To Endogenous Cancer-specific Dna Damagementioning

confidence: 99%

Targeting BER enzymes in cancer therapy

et al. 2018

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Base excision repair (BER) repairs mutagenic or genotoxic DNA base lesions, thought to be important for both the etiology and treatment of cancer. Cancer phenotypic stress induces oxidative lesions, and deamination products are responsible for one of the most prevalent mutational signatures in cancer. Chemotherapeutic agents induce genotoxic DNA base damage that are substrates for BER, while synthetic lethal approaches targeting BER-related factors are making their way into the clinic. Thus, there are three strategies by which BER is envisioned to be relevant in cancer chemotherapy: (i) to maintain cellular growth in the presence of endogenous DNA damage in stressed cancer cells, (ii) to maintain viability after exogenous DNA damage is introduced by therapeutic intervention, or (iii) to confer synthetic lethality in cancer cells that have lost one or more additional DNA repair pathways. Here, we discuss the potential treatment strategies, and briefly summarize the progress that has been made in developing inhibitors to core BER-proteins and related factors.

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“…Therefore, MTH1 has been explored as a potential cancer therapeutic target, and indeed inhibition of MTH1 by small molecules TH588 and TH287, the first-in-class nudix hydrolase family inhibitors, Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry causes incorporation of oxidized dNTPs in cancer cells leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse on xenografts [54,55]. Unfortunately, this finding has been seriously challenged by recent studies demonstrating that MTH1 is dispensable for cancer cell survival [56,57]. Thus, it remains to be established how much cancer cells really rely on MTH1 activity.…”

Section: Mth1 Mth2mentioning

confidence: 99%

Hepatitis B Virus X Protein Increases 8-Oxo-7,8-Dihydro-2ʹ-Deoxyguanosine (8-Oxodg) Level via Repressing MTH1/ MTH2 Expression in Hepatocytes

Lin

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Chronic hepatitis B virus (HBV) infection markedly increases the risk of development of hepatocellular carcinoma (HCC). Among the seven viral proteins that HBV encodes, HBV X protein (HBx) appears to have the most oncogenic potential. The mitochondria-associated HBx can induce oxidative stress in hepatocytes, leading to the production of abundant reactive oxygen species (ROS). High levels of ROS usually induce oxidative DNA damage and 8-hydroxy-2-deoxyguanosine (8-OHdG), also known as 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG), which is one of the major products of DNA oxidation and an important biomarker for oxidative stress and carcinogenesis. Cells have evolved a mechanism to prevent oxidized nucleotides from their incorporation into DNA through nucleotide pool sanitization enzymes of MTH1 (NUDT1), MTH2 (NUDT15), MTH3 (NUDT18) and NUDT5. However, little is known as to whether HBx can regulate the expression of those enzymes and modulate the formation and accumulation of 8-oxodG in hepatocytes. Methods: The level of 8-oxodG was assessed by ELISA in stable HBV-producing hepatoma cell lines, an HBV infectious mouse model, HBV and HBx transgenic mice and HBV-infected patients versus their respective controls. Expression of MTH1, MTH2, MTH3 and NUDT5 was determined by a real-time quantitative PCR and western blot analysis. Transcriptional regulation of MTH1 and MTH2 expression by HBx and the effect of HBx on MTH1 and MTH2 promoter hypermethylation were examined using a luciferase reporter assay and bisulfite sequencing analysis. Results: In comparison with controls, significantly higher levels of 8-oxodG were detected in the genome and culture supernatant of stable HBV-producing HepG2.2.15 cells, in the sera and liver tissues of HBV infectious mice and HBV or HBx transgenic mice, and in the sera of HBV-infected patients. Expression of HBx in hepatocytes significantly increased 8-oxodG level and reduced the expression of MTH1 and MTH2 at both mRNA and protein levels. It was also demonstrated that HBx markedly attenuated the MTH1 or MTH2 promoter activities through hypermethylation. Furthermore, enhancement of 8-oxodG production by HBx was reversible by overexpression of MTH1 and MTH2. Conclusion: Our data show that HBx expression results in the accumulation of 8-oxodG in hepatocytes through inhibiting the expression of MTH1 and MTH2. This may implicate that HBx may act as a tumor promoter through facilitating the mutational potential of 8-oxodG thus connecting a possible link between HBV infection and liver carcinogenesis.

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Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target

Cited by 50 publications

References 16 publications

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

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

Targeting BER enzymes in cancer therapy

Hepatitis B Virus X Protein Increases 8-Oxo-7,8-Dihydro-2ʹ-Deoxyguanosine (8-Oxodg) Level via Repressing MTH1/ MTH2 Expression in Hepatocytes

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