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).

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

Sainas S.;Giorgis M.;Circosta P.;Gaidano V.;Bonanni D.;Pippione A. C.;Qiu Y.;Cojocaru C. F.;Canepa B.;Rolando B.;Mishina M.;Ramondetti C.;Buccinna B.;Piccinini M.;Houshmand M.;Cignetti A.;Giraudo E.;Boschi D.;Saglio G.;Lolli M. L.
2021

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).
JOURNAL OF MEDICINAL CHEMISTRY
64
9
5404
5428
https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01549
Animals; Apoptosis; Binding Sites; Biphenyl Compounds; Cell Differentiation; Cell Line, Tumor; Drug Design; Enzyme Inhibitors; Female; Half-Life; Humans; Leukemia, Myeloid, Acute; Male; Mice; Mice, Inbred BALB C; Microsomes, Liver; Molecular Docking Simulation; Oxidoreductases Acting on CH-CH Group Donors; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship
Sainas S.; Giorgis M.; Circosta P.; Gaidano V.; Bonanni D.; Pippione A.C.; Bagnati R.; Passoni A.; Qiu Y.; Cojocaru C.F.; Canepa B.; Bona A.; Rolando B.; Mishina M.; Ramondetti C.; Buccinna B.; Piccinini M.; Houshmand M.; Cignetti A.; Giraudo E.; Al-Karadaghi S.; Boschi D.; Saglio G.; Lolli M.L.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1795212
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