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- Berglund, U. W., et al.
(författare)
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Validation and development of MTH1 inhibitors for treatment of cancer
- 2016
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 27:12, s. 2275-2283
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 2. |
- Michel, Maurice, et al.
(författare)
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Computational and Experimental Druggability Assessment of Human DNA Glycosylases
- 2019
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 4:7, s. 11642-11656
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Tidskriftsartikel (refereegranskat)abstract
- Due to a polar or even charged binding interface, DNA-binding proteins are considered extraordinarily difficult targets for development of small-molecule ligands and only a handful of proteins have been targeted successfully to date. Recently, however, it has been shown that development of selective and efficient inhibitors of 8-oxoguanine DNA glycosylase is possible. Here, we describe the initial druggability assessment of DNA glycosylases in a computational setting and experimentally investigate several methods to target endonuclease VIII-like 1 (NEIL1) with small-molecule inhibitors. We find that DNA glycosylases exhibit good predicted druggability in both DNA-bound and -unbound states. Furthermore, we find catalytic sites to be highly flexible, allowing for a range of interactions and binding partners. One flexible catalytic site was rationalized for NEIL1 and further investigated experimentally using both a biochemical assay in the presence of DNA and a thermal shift assay in the absence of DNA.
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| 5. |
- Toor, Salman, et al.
(författare)
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SNIC Science Cloud (SSC): A national-scale cloud infrastructure for Swedish academia
- 2017
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Ingår i: Proceedings - 13th IEEE International Conference on eScience, eScience 2017. - Los Alamitos, CA : IEEE Computer Society. ; , s. 219-227, s. 219-227
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Konferensbidrag (refereegranskat)abstract
- The cloud computing paradigm have fundamentally changed the way computational resources are being offered. Although the number of large-scale providers in academia is still relatively small, there is a rapidly increasing interest and adoption of cloud Infrastructure-as-a-Service in the scientific community. The added flexibility in how applications can be implemented compared to traditional batch computing systems is one of the key success factors for the paradigm, and scientific cloud computing promises to increase adoption of simulation and data analysis in scientific communities not traditionally users of large scale e-Infrastructure, the so called long tail of science. In 2014, the Swedish National Infrastructure for Computing (SNIC) initiated a project to investigate the cost and constraints of offering cloud infrastructure for Swedish academia. The aim was to build a platform where academics could evaluate cloud computing for their use-cases. SNIC Science Cloud (SSC) has since then evolved into a national-scale cloud infrastructure based on three geographically distributed regions. In this article we present the SSC vision, architectural details and user stories. We summarize the experiences gained from running a nationalscale cloud facility into ten simple rules for starting up a science cloud project based on OpenStack. We also highlight some key areas that require careful attention in order to offer cloud infrastructure for ubiquitous academic needs and in particular scientific workloads.
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