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

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

  • J Med Chem. 2018 Jul 26;61(14):6034-6055. doi: 10.1021/acs.jmedchem.8b00373.
Stefano Sainas,  Agnese C Pippione,  Elisa Lupino,  Marta Giorgis,  Paola Circosta 1 2,  Valentina Gaidano 3 4,  Parveen Goyal 5,  Davide Bonanni,  Barbara Rolando,  Alessandro Cignetti 3 4,  Alex Ducime,  Mikael Andersson 5,  Michael Järvå 6,  Rosmarie Friemann 5,  Marco Piccinini,  Cristina Ramondetti,  Barbara Buccinnà,  Salam Al-Karadaghi 7,  Donatella Boschi,  Giuseppe Saglio 3 4,  Marco L Lolli
Affiliations

Affiliations

  • 1 Department of Molecular Biotechnology and Health Sciences , University of Turin , Turin 10126 , Italy.
  • 2 Molecular Biotechnology Center , Turin 10126 , Italy.
  • 3 Department of Clinical and Biological Sciences , University of Turin , Turin 10043 , Italy.
  • 4 Mauriziano Hospital S.C.D.U. Hematology , Turin 10128 , Italy.
  • 5 Department of Chemistry and Molecular Biology , University of Gothenburg , Gothenburg SE 405 , Sweden.
  • 6 Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science , La Trobe University , Melbourne , Victoria 3086 , Australia.
  • 7 Department of Biochemistry and Structural Biology , Lund University , Lund 221 00 , Sweden.
PMID: 29939742 DOI: 10.1021/acs.jmedchem.8b00373
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[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.

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