Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5
| Autor: | Stefano, Sainas, Marta, Giorgis, Paola, Circosta, Valentina, Gaidano, Davide, Bonanni, Agnese C, Pippione, Renzo, Bagnati, Alice, Passoni, Yaqi, Qiu, Carina Florina, Cojocaru, Barbara, Canepa, Alessandro, Bona, Barbara, Rolando, Mariia, Mishina, Cristina, Ramondetti, Barbara, Buccinnà, Marco, Piccinini, Mohammad, Houshmand, Alessandro, Cignetti, Enrico, Giraudo, Salam, Al-Karadaghi, Donatella, Boschi, Giuseppe, Saglio, Marco L, Lolli |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Oxidoreductases Acting on CH-CH Group Donors Pyridines Dihydroorotate Dehydrogenase Apoptosis Article Rats Sprague-Dawley Mice Structure-Activity Relationship hemic and lymphatic diseases Cell Line Tumor Animals Humans Enzyme Inhibitors Mice Inbred BALB C Binding Sites Biphenyl Compounds Cell Differentiation Rats Molecular Docking Simulation Leukemia Myeloid Acute Drug Design Microsomes Liver Pyrazoles Female Half-Life |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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