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EnglishHuman dihydroorotate dehydrogenase (hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[l,5-a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of hDHODH inhibitors.
| Titolo: | Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors |
| Autori Riconosciuti: | |
| Autori: | Sainas, Stefano; Pippione, Agnese C; Lupino, Elisa; Giorgis, Marta; Circosta, Paola; Gaidano, Valentina; Goyal, Parveen; Bonanni, Davide; Rolando, Barbara; Cignetti, Alessandro; Ducime, Alex; Andersson, Mikael; Järvå, Michael; Friemann, Rosmarie; Piccinini, Marco; Ramondetti, Cristina; Buccinnà, Barbara; Al-Karadaghi, Salam; Boschi, Donatella; Saglio, Giuseppe; Lolli, Marco L |
| Data di pubblicazione: | 2018 |
| Abstract: | Human dihydroorotate dehydrogenase (hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[l,5-a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of hDHODH inhibitors. |
| Volume: | 61 |
| Fascicolo: | 14 |
| Pagina iniziale: | 6034-6055 |
| Pagina finale: | 6055 |
| Digital Object Identifier (DOI): | 10.1021/acs.jmedchem.8b00373 |
| URL: | https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00373 |
| Parole Chiave: | AUTOIMMUNE-DISEASES; HDHODH INHIBITORS; BREQUINAR SODIUM; CANCER-PATIENTS; DHODH; |
| Rivista: | JOURNAL OF MEDICINAL CHEMISTRY |
| Appare nelle tipologie: | 03A-Articolo su Rivista |
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