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
  • 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.