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 Aryloxyaryl Moiety
AU - Sainas, Stefano
AU - Giorgis, Marta
AU - Circosta, Paola
AU - Poli, Giulio
AU - Alberti, Marta
AU - Passoni, Alice
AU - Gaidano, Valentina
AU - Pippione, Agnese C.
AU - Vitale, Nicoletta
AU - Bonanni, Davide
AU - Rolando, Barbara
AU - Cignetti, Alessandro
AU - Ramondetti, Cristina
AU - Lanno, Alessia
AU - Ferraris, Davide M.
AU - Canepa, Barbara
AU - Buccinnà, Barbara
AU - Piccinini, Marco
AU - Rizzi, Menico
AU - Saglio, Giuseppe
AU - Al-Karadaghi, Salam
AU - Boschi, Donatella
AU - Miggiano, Riccardo
AU - Tuccinardi, Tiziano
AU - Lolli, Marco L.
PY - 2022/10/13
Y1 - 2022/10/13
N2 - In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 1.2 nM), we kept improving the structure-activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound 4 has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML.
AB - In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 1.2 nM), we kept improving the structure-activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound 4 has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML.
U2 - 10.1021/acs.jmedchem.2c00496
DO - 10.1021/acs.jmedchem.2c00496
M3 - Article
C2 - 36162075
AN - SCOPUS:85139185177
SN - 0022-2623
VL - 65
SP - 12701
EP - 12724
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 19
ER -