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

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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

Sammanfattning

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).

Originalspråkengelska
Sidor (från-till)5404-5428
Antal sidor25
TidskriftJournal of Medicinal Chemistry
Volym64
Nummer9
DOI
StatusPublished - 2021 maj

Ämnesklassifikation (UKÄ)

  • Hematologi

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