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Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5- a ]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors

2018; American Chemical Society; Volume: 61; Issue: 14 Linguagem: Inglês

10.1021/acs.jmedchem.8b00373

1520-4804

Stefano Sainas, Agnese Chiara Pippione, Elisa Lupino, Marta Giorgis, Paola Circosta, Valentina Gaidano, Parveen Goyal, Davide Bonanni, Barbara Rolando, Alessandro Cignetti, Alex Ducime, Mikael Andersson, Michael Järvå, Rosmarie Friemann, Marco Piccinini, Cristina Ramondetti, Barbara Buccinnà, Salam Al‐Karadaghi, Donatella Boschi, Giuseppe Saglio, Marco L. Lolli,

Signaling Pathways in Disease

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[1,5- 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.