Stefano Sainas1, Marta Giorgis1, Paola Circosta2,3, Valentina Gaidano2,4, Davide Bonanni1, Agnese C Pippione1, Renzo Bagnati5, Alice Passoni5, Yaqi Qiu6,7, Carina Florina Cojocaru6, Barbara Canepa8, Alessandro Bona9, Barbara Rolando1, Mariia Mishina1, Cristina Ramondetti10, Barbara Buccinnà10, Marco Piccinini10, Mohammad Houshmand2,3, Alessandro Cignetti11, Enrico Giraudo1,6, Salam Al-Karadaghi12, Donatella Boschi1, Giuseppe Saglio2,11, Marco L Lolli1. 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).
The connection with acute myelogenous leukemia (n class="Disease">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).
Authors: Stefano Sainas; Marta Giorgis; Paola Circosta; Giulio Poli; Marta Alberti; Alice Passoni; Valentina Gaidano; Agnese C Pippione; Nicoletta Vitale; Davide Bonanni; Barbara Rolando; Alessandro Cignetti; Cristina Ramondetti; Alessia Lanno; Davide M Ferraris; Barbara Canepa; Barbara Buccinnà; Marco Piccinini; Menico Rizzi; Giuseppe Saglio; Salam Al-Karadaghi; Donatella Boschi; Riccardo Miggiano; Tiziano Tuccinardi; Marco L Lolli Journal: J Med Chem Date: 2022-09-26 Impact factor: 8.039