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

• DOI: 10.1021/acs.jmedchem.0c01549
• Publication Date: 2021-04-15T06:15:45Z
• Authors: Stefano Sainas; Marta Giorgis; Paola Circosta; Valentina Gaidano; Davide Bonanni; Agnese C. Pippione; Renzo Bagnati; Alice Passoni; Yaqi Qiu; Carina Florina Co...; Barbara Canepa; Alessandro Bona; Barbara Rolando; Mariia Mishina; Cristina Ramondetti; Barbara Buccinnà; Marco Piccinini; Mohammad Houshmand; Alessandro Cignetti; Enrico Giraudo; Salam Al-Karadaghi; Donatella Boschi; Giuseppe Saglio; Marco L. Lolli
• Keywords: Dihydroorotate Dehydrogenase; Jurkat cells; IC50

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