| 1. |
- Calistri, A, et al.
(författare)
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The New Generation hDHODH Inhibitor MEDS433 Hinders the In Vitro Replication of SARS-CoV-2 and Other Human Coronaviruses
- 2021
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Ingår i: Microorganisms. - : MDPI AG. - 2076-2607. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- Although coronaviruses (CoVs) have long been predicted to cause zoonotic diseases and pandemics with high probability, the lack of effective anti-pan-CoVs drugs rapidly usable against the emerging SARS-CoV-2 actually prevented a promptly therapeutic intervention for COVID-19. Development of host-targeting antivirals could be an alternative strategy for the control of emerging CoVs infections, as they could be quickly repositioned from one pandemic event to another. To contribute to these pandemic preparedness efforts, here we report on the broad-spectrum CoVs antiviral activity of MEDS433, a new inhibitor of the human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidine biosynthesis pathway. MEDS433 inhibited the in vitro replication of hCoV-OC43 and hCoV-229E, as well as of SARS-CoV-2, at low nanomolar range. Notably, the anti-SARS-CoV-2 activity of MEDS433 against SARS-CoV-2 was also observed in kidney organoids generated from human embryonic stem cells. Then, the antiviral activity of MEDS433 was reversed by the addition of exogenous uridine or the product of hDHODH, the orotate, thus confirming hDHODH as the specific target of MEDS433 in hCoVs-infected cells. Taken together, these findings suggest MEDS433 as a potential candidate to develop novel drugs for COVID-19, as well as broad-spectrum antiviral agents exploitable for future CoVs threats.
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| 2. |
- Conteduca, V., et al.
(författare)
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Plasma tumour DNA as an early indicator of treatment response in metastatic castration-resistant prostate cancer
- 2020
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 123, s. 982-987
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Tidskriftsartikel (refereegranskat)abstract
- Background Plasma tumour DNA (ptDNA) levels on treatment are associated with response in a variety of cancers. However, the role of ptDNA in prostate cancer monitoring remains largely unexplored. Here we characterised on-treatment ptDNA dynamics and evaluated its potential for early assessment of therapy efficacy for metastatic castration-resistant prostate cancer (mCRPC). Methods Between 2011 and 2016, 114 sequential plasma samples from 43 mCRPC abiraterone-treated patients were collected. Targeted next-generation sequencing was performed to determine ptDNA fraction. ptDNA progressive disease was defined as a rise in the fraction compared to the pre-treatment. Results A ptDNA rise in the first on-treatment sample (interquartile range (IQR) 2.6-3.7 months) was significantly associated with increased risk of early radiographic or any prostate-specific antigen (PSA) rise (odds ratio (OR) = 15.8, 95% confidence interval (CI) 3.5-60.2,p = 0.0002 and OR = 6.0, 95% CI 1.6-20.0,p = 0.01, respectively). We also identified exemplar cases that had a rise in PSA or pseudoprogression secondary to bone flare but no rise in ptDNA. In an exploratory analysis, initial ptDNA change was found to associate with the duration of response to prior androgen deprivation therapy (p < 0.0001) but not to prior taxanes (p = 0.32). Conclusions We found that ptDNA assessment for therapy monitoring in mCRPC is feasible and provides data relevant to the clinical setting. Prospective evaluation of these findings is now merited.
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| 3. |
- Della Torre, S., et al.
(författare)
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An Essential Role for Liver ER alpha in Coupling Hepatic Metabolism to the Reproductive Cycle
- 2016
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 15:2, s. 360-371
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Tidskriftsartikel (refereegranskat)abstract
- Lipoprotein synthesis is controlled by estrogens, but the exact mechanisms underpinning this regulation and the role of the hepatic estrogen receptor alpha (ER alpha) in cholesterol physiology are unclear. Utilizing a mouse model involving selective ablation of ER alpha in the liver, we demonstrate that hepatic ER alpha couples lipid metabolism to the reproductive cycle. We show that this receptor regulates the synthesis of cholesterol transport proteins, enzymes for lipoprotein remodeling, and receptors for cholesterol uptake. Additionally, ER alpha is indispensable during proestrus for the generation of high-density lipoproteins efficient in eliciting cholesterol efflux from macrophages. We propose that a specific interaction with liver X receptor alpha (LXR alpha) mediates the broad effects of ER alpha on the hepatic lipid metabolism.
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| 4. |
- Pippione, Agnese C., et al.
(författare)
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Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors : Synthesis, biological evaluation and X-ray structural studies
- 2019
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 163, s. 266-280
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Tidskriftsartikel (refereegranskat)abstract
- Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) has been clinically validated as a target for antimalarial drug discovery, as a triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. Here, we have identified new hydroxyazole scaffold-based PfDHODH inhibitors belonging to two different chemical series. The first series was designed by a scaffold hopping strategy that exploits the use of hydroxylated azoles. Within this series, the hydroxythiadiazole 3 was identified as the best selective PfDHODH inhibitor (IC50 12.0 μM). The second series was designed by modulating four different positions of the hydroxypyrazole scaffold. In particular, hydroxypyrazoles 7e and 7f were shown to be active in the low μM range (IC50 2.8 and 5.3 μM, respectively). All three compounds, 3, 7e and 7f showed clear selectivity over human DHODH (IC50 > 200 μM), low cytotoxicity, and retained micromolar activity in P. falciparum-infected erythrocytes. The crystallographic structures of PfDHODH in complex with compounds 3 and 7e proved their binding mode, supplying essential data for future optimization of these scaffolds.
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| 5. |
- Sainas, Stefano, et al.
(författare)
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Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds
- 2017
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 129, s. 287-302
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Tidskriftsartikel (refereegranskat)abstract
- A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site. Initially, the inhibitory activity of the compounds was studied on recombinant hDHODH. The most potent compound of the series in the enzymatic assays was the thiadiazole analogue 4 (IC5016 nM). The activity was found to be dependent on the fluoro substitution pattern at the biphenyl moiety as well as on the choice/substitution of the heterocyclic ring. Structure determination of hDHODH co-crystallized with one representative compound from each series (4, 5 and 6) confirmed the brequinar-like binding mode as suggested by modelling. The specificity of the observed effects of the compound series was tested in cell-based assays for antiproliferation activity using Jurkat cells and PHA-stimulated PBMC. These tests were also verified by addition of exogenous uridine to the culture medium. In particular, the triazole analogue 6 (IC50against hDHODH: 45 nM) exerted potent in vitro antiproliferative and immunosuppressive activity without affecting cell survival.
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| 6. |
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| 7. |
- Lolli, M. L., et al.
(författare)
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Bioisosteres of Indomethacin as Inhibitors of Aldo-Keto Reductase 1C3
- 2019
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Ingår i: Acs Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 10:4, s. 437-443
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Tidskriftsartikel (refereegranskat)abstract
- Aldo-keto reductase 1C3 (AKR1C3) is an attractive target in drug design for its role in resistance to anticancer therapy. Several nonsteroidal anti-inflammatory drugs such as indomethacin are known to inhibit AKR1C3 in a nonselective manner because of COX-off target effects. Here we designed two indomethacin analogues by proposing a bioisosteric connection between the indomethacin carboxylic acid function and either hydroxyfurazan or hydroxy triazole rings. Both compounds were found to target AKR1C3 in a selective manner. In particular, hydroxyfurazan derivative is highly selective for AKR1C3 over the 1C2 isoform (up to 90-times more) and inactive on COX enzymes. High-resolution crystal structure of its complex with AKR1C3 shed light onto the binding mode of the new inhibitors. In cell-based assays (on colorectal and prostate cancer cells), the two indomethacin analogues showed higher potency than indomethacin. Therefore, these two AKR1C3 inhibitors can be used to provide further insight into the role of AKR1C3 in cancer. © 2019 American Chemical Society.
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| 8. |
- Pippione, Agnese C., et al.
(författare)
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4-Hydroxy-N -[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide: A novel inhibitor of the canonical NF-κB cascade
- 2017
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 8:9, s. 1850-1855
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Tidskriftsartikel (refereegranskat)abstract
- The NF-κB signaling pathway is a validated oncological target. Here, we applied scaffold hopping to IMD-0354, a presumed IKKβ inhibitor, and identified 4-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide (4) as a nM-inhibitor of the NF-κB pathway. However, both 4 and IMD-0354, being potent inhibitors of the canonical NF-κB pathway, were found to be inactive in human IKKβ enzyme assays.
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| 9. |
- Sainas, Stefano, et al.
(författare)
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Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold : SAR of the Aryloxyaryl Moiety
- 2022
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 65:19, s. 12701-12724
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 1.2 nM), we kept improving the structure-activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound 4 has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML.
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| 10. |
- Sainas, Stefano, et al.
(författare)
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Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold : SAR of the Biphenyl Moiety
- 2021
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:9, s. 5404-5428
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Tidskriftsartikel (refereegranskat)abstract
- The connection with acute myelogenous leukemia (AML) of dihydroorotate dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharma as a possible AML therapeutic target. We recently discovered compound 1, a potent hDHODH inhibitor (IC50 = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1) in the low nM range (EC50 = 32.8 nM) superior to brequinar's phase I/II clinical trial (EC50 = 265 nM). Herein, we investigate the 1 drug-like properties observing good metabolic stability and no toxic profile when administered at doses of 10 and 25 mg/kg every 3 days for 5 weeks (Balb/c mice). Moreover, in order to identify a backup compound, we investigate the SAR of this class of compounds. Inside the series, 17 is characterized by higher potency in inducing myeloid differentiation (EC50 = 17.3 nM), strong proapoptotic properties (EC50 = 20.2 nM), and low cytotoxicity toward non-AML cells (EC30(Jurkat) > 100 μM).
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