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

  • J Med Chem. 2021 May 13;64(9):5404-5428. doi: 10.1021/acs.jmedchem.0c01549.
Stefano Sainas  1 ,  Marta Giorgis  1 ,  Paola Circosta  2  3 ,  Valentina Gaidano  2  4 ,  Davide Bonanni  1 ,  Agnese C Pippione  1 ,  Renzo Bagnati  5 ,  Alice Passoni  5 ,  Yaqi Qiu  6  7 ,  Carina Florina Cojocaru  6 ,  Barbara Canepa  8 ,  Alessandro Bona  9 ,  Barbara Rolando  1 ,  Mariia Mishina  1 ,  Cristina Ramondetti  10 ,  Barbara Buccinnà  10 ,  Marco Piccinini  10 ,  Mohammad Houshmand  2  3 ,  Alessandro Cignetti  11 ,  Enrico Giraudo  1  6 ,  Salam Al-Karadaghi  12 ,  Donatella Boschi  1 ,  Giuseppe Saglio  2  11 ,  Marco L Lolli  1
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. Division of Hematology, AO SS Antonio e Biagio e Cesare Arrigo, Via Venezia 16, Alessandria 15121, Italy.
  • 5. Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milano 20156, Italy.
  • 6. Laboratory of Tumor Microenvironment, Candiolo Cancer Institute, FPO, IRCCS, Candiolo, Strada Provinciale, 142-KM 3.95, Candiolo, Turin 10060, Italy.
  • 7. Higher Education Mega Center, Institutes for Life Sciences, South China University of Technology, Guangzhou 510641, China.
  • 8. Gem Forlab srl, Via Ribes, 5, Colleretto Giacosa, Turin 10010, Italy.
  • 9. Gem Chimica srl, Via Maestri del Lavoro, 25, Busca, Cuneo 12022, Italy.
  • 10. Department of Oncology, University of Turin, Via Michelangelo 27/B, Turin 10125, Italy.
  • 11. Division of Hematology and Cell Therapy, AO Ordine Mauriziano, Largo Filippo Turati, 62, Turin 10128, Italy.
  • 12. Department of Biochemistry and Structural Biology, Lund University, Naturvetarvägen 14, Box 124, Lund 221 00, Sweden.
PMID: 33844533 DOI: 10.1021/acs.jmedchem.0c01549
Abstract

The connection with acute myelogenous leukemia (AML) of Dihydroorotate Dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharma as a possible AML therapeutic target. We recently discovered compound 1, a potent hDHODH inhibitor (IC50 = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1) in the low nM range (EC50 = 32.8 nM) superior to brequinar's phase I/II clinical trial (EC50 = 265 nM). Herein, we investigate the 1 drug-like properties observing good metabolic stability and no toxic profile when administered at doses of 10 and 25 mg/kg every 3 days for 5 weeks (Balb/c mice). Moreover, in order to identify a backup compound, we investigate the SAR of this class of compounds. Inside the series, 17 is characterized by higher potency in inducing myeloid differentiation (EC50 = 17.3 nM), strong proapoptotic properties (EC50 = 20.2 nM), and low cytotoxicity toward non-AML cells (EC30(Jurkat) > 100 μM).