TY - JOUR
T1 - Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold
T2 - SAR of the Biphenyl Moiety
AU - Sainas, Stefano
AU - Giorgis, Marta
AU - Circosta, Paola
AU - Gaidano, Valentina
AU - Bonanni, Davide
AU - Pippione, Agnese C.
AU - Bagnati, Renzo
AU - Passoni, Alice
AU - Qiu, Yaqi
AU - Cojocaru, Carina Florina
AU - Canepa, Barbara
AU - Bona, Alessandro
AU - Rolando, Barbara
AU - Mishina, Mariia
AU - Ramondetti, Cristina
AU - Buccinnà, Barbara
AU - Piccinini, Marco
AU - Houshmand, Mohammad
AU - Cignetti, Alessandro
AU - Giraudo, Enrico
AU - Al-Karadaghi, Salam
AU - Boschi, Donatella
AU - Saglio, Giuseppe
AU - Lolli, Marco L.
PY - 2021/5
Y1 - 2021/5
N2 - 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).
AB - 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).
U2 - 10.1021/acs.jmedchem.0c01549
DO - 10.1021/acs.jmedchem.0c01549
M3 - Article
C2 - 33844533
AN - SCOPUS:85102878882
VL - 64
SP - 5404
EP - 5428
JO - Journal of Medicinal and Pharmaceutical Chemistry
JF - Journal of Medicinal and Pharmaceutical Chemistry
SN - 1520-4804
IS - 9
ER -