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.

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

Sainas, Stefano;Pippione, Agnese C;Lupino, Elisa;Giorgis, Marta;Circosta, Paola;Gaidano, Valentina;Bonanni, Davide;Rolando, Barbara;Ducime, Alex;Piccinini, Marco;Ramondetti, Cristina;Buccinnà, Barbara;Al-Karadaghi, Salam;Boschi, Donatella;Saglio, Giuseppe;Lolli, Marco L
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.
JOURNAL OF MEDICINAL CHEMISTRY
61
14
6034-6055
6055
https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00373
AUTOIMMUNE-DISEASES; HDHODH INHIBITORS; BREQUINAR SODIUM; CANCER-PATIENTS; DHODH;
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
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1686360
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