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  2. 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

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

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.
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).

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