[HTML][HTML] Validation and development of MTH1 inhibitors for treatment of cancer
UW Berglund, K Sanjiv, H Gad, C Kalderen… - Annals of oncology, 2016 - Elsevier
Annals of oncology, 2016•Elsevier
Different MTH1 inhibitors have different ability to kill cancer cells. Here we demonstrate that
the lack of efficiency of some MTH1 inhibitors is explained by their inability introduce the
toxic oxidized nucleotides into DNA. Furthermore, we describe TH1579, Karonudib, which is
a potent, selective MTH1 inhibitor with good oral availability and with excellent anti-cancer
properties in vivo. Background Previously, we showed cancer cells rely on the MTH1 protein
to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we …
the lack of efficiency of some MTH1 inhibitors is explained by their inability introduce the
toxic oxidized nucleotides into DNA. Furthermore, we describe TH1579, Karonudib, which is
a potent, selective MTH1 inhibitor with good oral availability and with excellent anti-cancer
properties in vivo. Background Previously, we showed cancer cells rely on the MTH1 protein
to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we …
Abstract
Different MTH1 inhibitors have different ability to kill cancer cells. Here we demonstrate that the lack of efficiency of some MTH1 inhibitors is explained by their inability introduce the toxic oxidized nucleotides into DNA. Furthermore, we describe TH1579, Karonudib, which is a potent, selective MTH1 inhibitor with good oral availability and with excellent anti-cancer properties in vivo.
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.
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