Identification of potent and selective MTH1 inhibitors

Petrocchi, Alessia; Leo, Elisabetta; Reyna, Naphtali J.; Hamilton, Matthew M.; Shi, Xi; Parker, Connor A.; Mseeh, Faika; Bardenhagen, Jennifer; Leonard, Paul G.; Cross, Jason B.; Huang, Sha; Jiang, Yongying; Cardozo, Mario; Draetta, Giulio; Marszalek, Joseph R.; Toniatti, Carlo; Jones, Philip; Lewis, Richard T.

doi:10.1016/j.bmcl.2016.02.026

Cited by 70 publications

(79 citation statements)

References 11 publications

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“…Finally, we note that a key difference between the studies that show a tumor-suppressive effect of MTH1 inhibition (including ours) [27,35,36,42] and those that do not [37,38,39] is that the former studies explicitly test effects of MTH1 inhibition in in vivo tumor formation models, whereas the latter solely utilize in vitro models (see Table 1). We have shown that a fairly modest in vitro proliferative defect (particularly in p53-nonfunctional cell lines, which many of the conflicting studies utilize) can manifest as a strong defect in in vivo tumor formation [27].…”

Section: Molecular and Cellular Contexts Underlying The Outcomes Omentioning

confidence: 99%

“…These reports were followed by additional studies describing the effects of additional small-molecule MTH1 inhibitors or the targeted inhibition of MTH1 via shRNA, siRNA, or CRISPR in a wide variety of cancer cell lines [37,38,39], ostensibly producing variable and inconsistent outcomes with regards to cell viability, often in the same cell lines (models, methodology and outcomes are summarized in Table 1). …”

Section: Outcomes Of Mth1 Inhibitors In Different Cancer Modelsmentioning

confidence: 99%

“…Petrocchi et al at MD Anderson also reported their in-house MTH1 inhibitors, IACS-4619 and IACS-4759 [39]. Both of these compounds apparently inhibited MTH1 activity more effectively than TH588 and TH287 (with IC50 values 2.5–8 times lower than TH287).…”

Section: Outcomes Of Mth1 Inhibitors In Different Cancer Modelsmentioning

confidence: 99%

“…The source of this inconsistency between the two studies could be due to the different cell lines (HeLa [37] vs. HCT116 [42]), drug doses and time points (TH287 at 3 µM for 18 h [37] vs. TH588 at 5 µM for 72 h [42]) and, potentially, the actual methods used for proteomic profiling. Finally, Warpman et al reported that, unlike TH588, several of the MTH1 inhibitors that did not induce cytotoxicity [38,39] also did not elevate 8-oxo-dGTP incorporation into genomic DNA, a critical factor in order for MTH1 inhibition to induce DNA breaks and tumor suppressor responses [30]. However, given the relative potencies of the other MTH1 inhibitors, some of which are able to inhibit MTH1 activity as well as, or better [39] than, TH588 and TH287, it is unclear why MTH1 inhibition by these compounds is unable to elevate oxidized nucleotides and their subsequent incorporation into genomic DNA.…”

Section: Outcomes Of Mth1 Inhibitors In Different Cancer Modelsmentioning

confidence: 99%

“…Finally, Warpman et al reported that, unlike TH588, several of the MTH1 inhibitors that did not induce cytotoxicity [38,39] also did not elevate 8-oxo-dGTP incorporation into genomic DNA, a critical factor in order for MTH1 inhibition to induce DNA breaks and tumor suppressor responses [30]. However, given the relative potencies of the other MTH1 inhibitors, some of which are able to inhibit MTH1 activity as well as, or better [39] than, TH588 and TH287, it is unclear why MTH1 inhibition by these compounds is unable to elevate oxidized nucleotides and their subsequent incorporation into genomic DNA. This issue (and other paradoxical and conflicting observations discussed above) can only be resolved if there is greater consistency among these studies across multiple experimental parameters, including drug concentrations, siRNA sequences, molecular profiling methodology, and common authenticated cell lines.…”

Section: Outcomes Of Mth1 Inhibitors In Different Cancer Modelsmentioning

confidence: 99%

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MTH1 as a Chemotherapeutic Target: The Elephant in the Room

Samaranayake

Huynh

Rai

2017

Cancers

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Many tumors sustain elevated levels of reactive oxygen species (ROS), which drive oncogenic signaling. However, ROS can also trigger anti-tumor responses, such as cell death or senescence, through induction of oxidative stress and concomitant DNA damage. To circumvent the adverse consequences of elevated ROS levels, many tumors develop adaptive responses, such as enhanced redox-protective or oxidatively-generated damage repair pathways. Targeting these enhanced oxidative stress-protective mechanisms is likely to be both therapeutically effective and highly specific to cancer, as normal cells are less reliant on such mechanisms. In this review, we discuss one such stress-protective protein human MutT Homolog1 (MTH1), an enzyme that eliminates 8-oxo-7,8-dihydro-2’-deoxyguanosine triphosphate (8-oxodGTP) through its pyrophosphatase activity, and is found to be elevated in many cancers. Our studies, and subsequently those of others, identified MTH1 inhibition as an effective tumor-suppressive strategy. However, recent studies with the first wave of MTH1 inhibitors have produced conflicting results regarding their cytotoxicity in cancer cells and have led to questions regarding the validity of MTH1 as a chemotherapeutic target. To address the proverbial "elephant in the room" as to whether MTH1 is a bona fide chemotherapeutic target, we provide an overview of MTH1 function in the context of tumor biology, summarize the current literature on MTH1 inhibitors, and discuss the molecular contexts likely required for its efficacy as a therapeutic target.

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Section: Molecular and Cellular Contexts Underlying The Outcomes Omentioning

confidence: 99%

Section: Outcomes Of Mth1 Inhibitors In Different Cancer Modelsmentioning

confidence: 99%

Section: Outcomes Of Mth1 Inhibitors In Different Cancer Modelsmentioning

confidence: 99%

Section: Outcomes Of Mth1 Inhibitors In Different Cancer Modelsmentioning

confidence: 99%

Section: Outcomes Of Mth1 Inhibitors In Different Cancer Modelsmentioning

confidence: 99%

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MTH1 as a Chemotherapeutic Target: The Elephant in the Room

Samaranayake

Huynh

Rai

2017

Cancers

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2‐Aminopyrimidines

2018

Privileged Structures in Drug Discovery

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HIF2α promotes tumour growth in clear cell renal cell carcinoma by increasing the expression of NUDT1 to reduce oxidative stress

Shi

Zhang

Wang

et al. 2021

Clinical & Translational Med

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BackgroundThe key role of hypoxia‐inducible factor 2alpha (HIF2α) in the process of renal cancer has been confirmed. In the field of tumour research, oxidative stress is also considered to be an important influencing factor. However, the relationship and biological benefits of oxidative stress and HIF2α in ccRCC remain unclear. This research attempts to explore the effect of oxidative stress on the cancer‐promoting effect of HIF2α in ccRCC and reveal its mechanism of action.MethodsThe bioinformatics analysis for ccRCC is based on whole transcriptome sequencing and TCGA database. The detection of the expression level of related molecules is realised by western blot and PCR. The expression of Nucleoside diphosphate‐linked moiety X‐type motif 1 (NUDT1) was knocked down by lentiviral infection technology. The functional role of NUDT1 were further investigated by CCK8 assays, transwell assays and cell oxidative stress indicator detection. The exploration of related molecular mechanisms is realised by Luciferase assays and Chromatin immunoprecipitation (ChIP) assays.ResultsMolecular screening based on knockdown HIF2α sequencing data and oxidative stress related data sets showed that NUDT1 is considered to be an important molecule for the interaction of HIF2α with oxidative stress. Subsequent experimental results showed that NUDT1 can cooperate with HIF2α to promote the progression of ccRCC. And this biological effect was found to be caused by the oxidative stress regulated by NUDT1. Mechanistically, HIF2α transcription activates the expression of NUDT1, thereby inhibiting oxidative stress and promoting the progression of ccRCC.ConclusionsThis research clarified a novel mechanism by which HIF2α stabilises sirtuin 3 (SIRT3) through direct transcriptional activation of NUDT1, thereby inhibiting oxidative stress to promote the development of ccRCC. It provided the possibility for the selection of new therapeutic targets for ccRCC and the study of combination medication regimens.

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Identification of potent and selective MTH1 inhibitors

Cited by 70 publications

References 11 publications

MTH1 as a Chemotherapeutic Target: The Elephant in the Room

MTH1 as a Chemotherapeutic Target: The Elephant in the Room

2‐Aminopyrimidines

HIF2α promotes tumour growth in clear cell renal cell carcinoma by increasing the expression of NUDT1 to reduce oxidative stress

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