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

作者：Sainas, Stefano; Giorgis, Marta; Circosta, Paola; Gaidano, Valentina; Bonanni, Davide; Pippione, Agnese C.; Bagnati, Renzo; Passoni, Alice; Qiu, Yaqi; Cojocaru, Carina Florina; Canepa, Barbara; Bona, Alessandro; Rolando, Barbara; Mishina, Mariia; Ramondetti, Cristina; Buccinna, Barbara; Piccinini, Marco; Houshmand, Mohammad; Cignetti, Alessandro; Giraudo, Enrico; Al-Karadaghi, Salam; Boschi, Donatella; Saglio, Giuseppe; Lolli, Marco L.^*

来源：Journal of Medicinal Chemistry, 2021, 64(9): 5404-5428.

DOI：10.1021/acs.jmedchem.0c01549

• ACUTE PROMYELOCYTIC LEUKEMIA
• ACCURATE DOCKING
• ARSENIC TRIOXIDE
• DHODH INHIBITOR
• RETINOIC ACID
• DIFFERENTIATION
• DESIGN
• MICRODOMAIN
• DERIVATIVES
• PROTEIN

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 mu M).

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