| 1. |
- Michel, M., et al.
(författare)
-
Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
- 2022
-
Ingår i: Science. - Stockholm : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 376:6600, s. 1471-1476
-
Tidskriftsartikel (refereegranskat)abstract
- Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging. © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
|
|
| 2. |
- Berglund, U. W., et al.
(författare)
-
Validation and development of MTH1 inhibitors for treatment of cancer
- 2016
-
Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 27:12, s. 2275-2283
-
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.
|
|
| 3. |
- Bonagas, Nadilly, et al.
(författare)
-
Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
-
Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
-
Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Scaletti, Emma Rose, et al.
(författare)
-
The First Structure of Human MTHFD2L and Its Implications for the Development of Isoform-Selective Inhibitors
- 2022
-
Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 17:18
-
Tidskriftsartikel (refereegranskat)abstract
- Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial 1-carbon metabolism enzyme, which is an attractive anticancer drug target as it is highly upregulated in cancer but is not expressed in healthy adult cells. Selective MTHFD2 inhibitors could therefore offer reduced side-effects during treatment, which are common with antifolate drugs that target other 1C-metabolism enzymes. This task is challenging however, as MTHFD2 shares high sequence identity with the constitutively expressed isozymes cytosolic MTHFD1 and mitochondrial MTHFD2L. In fact, one of the most potent MTHFD2 inhibitors reported to date, TH7299, is actually more active against MTHFD1 and MTHFD2L. While structures of MTHFD2 and MTHFD1 exist, no MTHFD2L structures are available. We determined the first structure of MTHFD2L and its complex with TH7299, which reveals the structural basis for its highly potent MTHFD2L inhibition. Detailed analysis of the MTHFD2L structure presented here clearly highlights the challenges associated with developing truly isoform-selective MTHFD2 inhibitors.
|
|
| 9. |
- Tampere, M, et al.
(författare)
-
Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses
- 2020
-
Ingår i: Viruses. - : MDPI AG. - 1999-4915. ; 12:12
-
Tidskriftsartikel (refereegranskat)abstract
- Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus (EBOV) have caused worldwide health emergencies highlighting the urgent need for new antiviral strategies. Targeting host cell pathways supporting viral replication is an attractive approach for development of antiviral compounds, especially with new, unexplored viruses where knowledge of virus biology is limited. Here, we present a strategy to identify host-targeted small molecule inhibitors using an image-based phenotypic antiviral screening assay followed by extensive target identification efforts revealing altered cellular pathways upon antiviral compound treatment. The newly discovered antiviral compounds showed broad-range antiviral activity against pathogenic RNA viruses such as SARS-CoV-2, EBOV and Crimean-Congo hemorrhagic fever virus (CCHFV). Target identification of the antiviral compounds by thermal protein profiling revealed major effects on proteostasis pathways and disturbance in interactions between cellular HSP70 complex and viral proteins, illustrating the supportive role of HSP70 on many RNA viruses across virus families. Collectively, this strategy identifies new small molecule inhibitors with broad antiviral activity against pathogenic RNA viruses, but also uncovers novel virus biology urgently needed for design of new antiviral therapies.
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
- Dhiman, Vinit, et al.
(författare)
-
Multiband optical variability of the TeV blazar PG 1553+113 in 2019
- 2022
-
Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 519:2, s. 2796-2811
-
Tidskriftsartikel (refereegranskat)abstract
- We report the flux and spectral variability of PG 1553 + 113 on intra-night (IDV) to short-term time-scales using BVRI data collected over 91 nights from 28 February to 8 November 2019 employing 10 optical telescopes: three in Bulgaria, two each in India and Serbia, and one each in Greece, Georgia, and Latvia. We monitored the blazar quasi-simultaneously for 16 nights in the V and R bands and 8 nights in the V, R, I bands and examined the light curves (LCs) for intra-day flux and colour variations using two powerful tests: the power-enhanced F-test and the nested ANOVA test. The source was found to be significantly (>99 per cent) variable in 4 nights out of 27 in R-band, 1 out of 16 in V-band, and 1 out of 6 nights in I-band. No temporal variations in the colours were observed on IDV time-scale. During the course of these observations the total variation in R-band was 0.89 mag observed. We also investigated the spectral energy distribution (SED) using B-, V-, R-, and I-band data. We found optical spectral indices in the range of 0.878 +/- 0.029 to 1.106 +/- 0.065 by fitting a power law (F-nu proportional to nu(-alpha)) to these SEDs of PG 1553 + 113. We found that the source follows a bluer-when-brighter trend on IDV time-scales. We discuss possible physical causes of the observed spectral variability.
|
|
| 13. |
|
|
| 14. |
- Gad, Helge, et al.
(författare)
-
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
-
Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
-
Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
|
|
| 15. |
- Gupta, Alok C., et al.
(författare)
-
Long-term Multiband Near-infrared Variability of the Blazar OJ 287 during 2007-2021
- 2022
-
Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 260:2, s. 39-
-
Tidskriftsartikel (refereegranskat)abstract
- We present the most extensive and well-sampled long-term multiband near-infrared (NIR) temporal and spectral variability study of OJ 287, considered to be the best candidate binary supermassive black hole blazar. These observations were made between 2007 December and 2021 November. The source underwent similar to 2-2.5 mag variations in the J, H, and Ks NIR bands. Over these long-term timescales there were no systematic trends in either flux or spectral evolution with time or with the source's flux states. However, on shorter timescales, there are significant variations in flux and spectra indicative of strong changes during different activity states. The NIR spectral energy distributions show diverse facets at each flux state, from the lowest to the highest. The spectra are, in general, consistent with a power-law spectral profile (within 10%) and many of them indicate minor changes (observationally insignificant) in the shift of the peak. The NIR spectra generally steepen during bright phases. We briefly discuss these behaviors in the context of blazar emission scenarios/mechanisms, OJ 287's well-known traditional behavior, and implications for models of the source central engine invoked for its long-term optical semiperiodic variations.
|
|
| 16. |
- Gupta, Alok C., et al.
(författare)
-
Multiband optical variability of the blazar OJ 287 during its outbursts in 2015-2016
- 2017
-
Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 465:4, s. 4423-4433
-
Tidskriftsartikel (refereegranskat)abstract
- We present recent optical photometric observations of the blazar OJ 287 taken during 2015 September-2016 May. Our intense observations of the blazar started in 2015 November and continued until 2016 May and included detection of the large optical outburst in 2015 December that was predicted using the binary black hole model for OJ 287. For our observing campaign, we used a total of nine ground-based optical telescopes of which one is in Japan, one is in India, three are in Bulgaria, one is in Serbia, one is in Georgia, and two are in the USA. These observations were carried out in 102 nights with a total of similar to 1000 image frames in BVRI bands, though the majority were in the R band. We detected a second comparably strong flare in 2016 March. In addition, we investigated multiband flux variations, colour variations, and spectral changes in the blazar on diverse time-scales as they are useful in understanding the emission mechanisms. We briefly discuss the possible physical mechanisms most likely responsible for the observed flux, colour, and spectral variability.
|
|
| 17. |
|
|
| 18. |
|
|
| 19. |
- Visnes, Torkild, et al.
(författare)
-
Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation
- 2018
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 362:6416, s. 834-
-
Tidskriftsartikel (refereegranskat)abstract
- The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor-alpha-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor kappa B and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.
|
|
| 20. |
- Visnes, Torkild, et al.
(författare)
-
Targeting OGG1 arrests cancer cell proliferation by inducing replication stress
- 2020
-
Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 48:21, s. 12234-12251
-
Tidskriftsartikel (refereegranskat)abstract
- Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.
|
|
