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Targeting myeloid differentiation using potent 2-hydroxypyrazolo[1,5-a]pyridine scaffold-based human dihydroorotate dehydrogenase (hDHODH) inhibitors.

Artikel i vetenskaplig tidskrift
Författare 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
Publicerad i Journal of medicinal chemistry
Volym 61
Nummer/häfte 14
Sidor 6034–6055
ISSN 1520-4804
Publiceringsår 2018
Publicerad vid Institutionen för kemi och molekylärbiologi
Sidor 6034–6055
Språk en
Länkar dx.doi.org/10.1021/acs.jmedchem.8b0...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Strukturbiologi, Organisk kemi, Läkemedelskemi

Sammanfattning

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 paper reports the design, synthesis, SAR, X-ray crystallography, biological assays and physicochemical characterization of the new class of hDHODH inhibitors.

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