New Quinolinone O-GlcNAc Transferase Inhibitors Based on Fragment Growth
| Autor: | Marko Anderluh, Cyril Balsollier, Elena M. Loi, Martina Gobec, Tihomir Tomašič, Roland J. Pieters, Matjaž Weiss, Maša Sterle |
|---|---|
| Přispěvatelé: | Afd Chemical Biology and Drug Discovery, Chemical Biology and Drug Discovery |
| Rok vydání: | 2021 |
| Předmět: |
glikozirani proteini
fragmentna rast molekularno sidranje O-GlcNAc transferaza molekularno sidranje Chemistry(all) Binding pocket udc:616-097 Farmacevtska kemija Imunski sistem 010402 general chemistry O-GlcNAc transferase 01 natural sciences fragmentna rast lcsh:Chemistry 03 medical and health sciences Immune system protein glycosylation Glycosyltransferase Potency Transferase IC50 Original Research 030304 developmental biology O-GlcNAc O-GlcNAc transferase protein glycosylation fragments growth molecular docking chemistry.chemical_classification O-GlcNAc transferaza 0303 health sciences udc:615.4:54:616-097 biology Chemistry General Chemistry molecular docking fragments growth 0104 chemical sciences Enzyme lcsh:QD1-999 Biochemistry glikozirani proteini biology.protein O-GlcNAc OGT GlcNAcylation O-GlcNAc Transferase OGT inhibitor Assay |
| Zdroj: | Frontiers in Chemistry Frontiers in Chemistry, 9, 1. Frontiers Media S.A. Frontiers in Chemistry, Vol 9 (2021) Frontiers in chemistry, vol. 9, pp. 1-8, 2021. Frontiers in chemistry, str. 1-8, Vol. 9, 2021 COBISS-ID: 1647919 |
| ISSN: | 2296-2646 |
| DOI: | 10.3389/fchem.2021.666122 |
| Popis: | O-GlcNAcylation is an important posttranslational and metabolic process in cells that must be carefully regulated. O-GlcNAc transferase (OGT) is ubiquitously present in cells and is the only enzyme that catalyzes the transfer of O-GlcNAc to proteins. OGT is a promising target in various pathologies such as cancer, immune system diseases, or nervous impairment. In our previous, work we identified the 2-oxo-1,2-dihydroquinoline-4-carboxamide derivatives as promising compounds by a fragment-based drug design approach. Herein, we report the extension of this first series with several new fragments. As the most potent fragment, we identified 3b with an IC50 value of 116.0 [micro]M. If compared with the most potent inhibitor of the first series, F20 (IC50 = 117.6 [micro]M), we can conclude that the new fragments did not improve OGT inhibition remarkably. Therefore, F20 was used as the basis for the design of a series of compounds with the elongation towards the O-GlcNAc binding pocket as the free carboxylate allows easy conjugation. Compound 6b with an IC50 value of 144.5 [micro]M showed the most potent OGT inhibition among the elongated compounds, but it loses inhibition potency when compared to the UDP mimetic F20. We therefore assume that the binding of the compounds in the O-GlcNAc binding pocket is likely not crucial for OGT inhibition. Furthermore, evaluation of the compounds with two different assays revealed that some inhibitors most likely interfere with the commercially available UDP-Glo glycosyltransferase assay, leading to false positive results. This observation calls for caution, when evaluating UDP mimetic as OGT inhibitors with the UDP-Glo glycosyltransferase assay, as misinterpretations can occur. Nasl. z nasl. zaslona. Opis vira z dne 18. 3. 2021. This research was funded by the Slovenian Research Agency, grant number P1-0208 and from the European Union's Horizon2020 programme under the Marie Skłodowska-Curie Grant Agreement No. 765581 (project PhD4GlycoDrug; www.phd4glycodrug.eu). MW acknowledged Young researcher postgraduate research funding granted by the Slovenian Research Agency No. 50503. Št. članka: 666122. Bibliografija: str. 7-8. Abstract. ARRS, Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin European Union’s Horizon2020 programme under the Marie Skłodowska-Curie, PhD4GlycoDrug; www.phd4glycodrug.eu |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|