2. Academic Validation
  3. Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold: SAR of the Aryloxyaryl Moiety

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold: SAR of the Aryloxyaryl Moiety

  • J Med Chem. 2022 Oct 13;65(19):12701-12724. doi: 10.1021/acs.jmedchem.2c00496.
Stefano Sainas 1,  Marta Giorgis 1,  Paola Circosta 2 3,  Giulio Poli 4,  Marta Alberti 5,  Alice Passoni 6,  Valentina Gaidano 7,  Agnese C Pippione 1,  Nicoletta Vitale 8,  Davide Bonanni 1 9,  Barbara Rolando 1,  Alessandro Cignetti 7,  Cristina Ramondetti 10,  Alessia Lanno 6,  Davide M Ferraris 5,  Barbara Canepa 11,  Barbara Buccinnà 10,  Marco Piccinini 10,  Menico Rizzi 5,  Giuseppe Saglio 2 7,  Salam Al-Karadaghi 12,  Donatella Boschi 1,  Riccardo Miggiano 5,  Tiziano Tuccinardi 3,  Marco L Lolli 1
Affiliations

Affiliations

  • 1 Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, Turin 10125, Italy.
  • 2 Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, Orbassano, Turin 10043, Italy.
  • 3 Molecular Biotechnology Center, University of Turin, Via Nizza 52, Turin 10126, Italy.
  • 4 Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy.
  • 5 Department of Pharmaceutical Sciences, University of Piemonte Orientale, Via G. Bovio 6, Novara 28100, Italy.
  • 6 Laboratory of Mass Spectrometry, Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan 20156, Italy.
  • 7 Division of Hematology and Cell Therapy, AO Ordine Mauriziano, Largo Filippo Turati, 62, Turin 10128, Italy.
  • 8 Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza 52, Turin 10126, Italy.
  • 9 Life Science Department, University of Modena, Via Università 4, Modena 41121, Italy.
  • 10 Department of Oncology, University of Turin, Via Michelangelo 27/B, Turin 10125, Italy.
  • 11 GEM FORLAB, Via Ing. Comotto 36, Caluso, Turin, 10014, Italy.
  • 12 Department of Biochemistry and Structural Biology, Lund University, Naturvetarvägen 14, Box 124, Lund 221 00, Sweden.
PMID: 36162075 DOI: 10.1021/acs.jmedchem.2c00496
Abstract

In recent years, human Dihydroorotate Dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 1.2 nM), we kept improving the structure-activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound 4 has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML.

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