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-act i v i t y 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.

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold: SAR of the Aryloxyaryl Moiety

Sainas, Stefano
Co-first
;
Giorgis, Marta
Co-first
;
Circosta, Paola;Alberti, Marta;Gaidano, Valentina;Pippione, Agnese C;Vitale, Nicoletta;Bonanni, Davide;Rolando, Barbara;Cignetti, Alessandro;Ramondetti, Cristina;Canepa, Barbara;Buccinnà, Barbara;Piccinini, Marco;Saglio, Giuseppe;Al-Karadaghi, Salam;Boschi, Donatella;Lolli, Marco L
2022-01-01

Abstract

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-act i v i t y 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.
2022
65
19
12701
12724
https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.2c00496
Animals; Antiviral Agents; Dihydroorotate Dehydrogenase; Dipyridamole; Enzyme Inhibitors; Humans; Mice; Pyridines; Structure-Activity Relationship; Leukemia, Myeloid, Acute; Oxidoreductases Acting on CH-CH Group Donors
Sainas, Stefano; Giorgis, Marta; Circosta, Paola; Poli, Giulio; Alberti, Marta; Passoni, Alice; Gaidano, Valentina; Pippione, Agnese C; Vitale, Nicole...espandi
File in questo prodotto:
File Dimensione Formato  
acs.jmedchem.2c00496.pdf

Accesso aperto

Descrizione: Articolo su Rivista
Tipo di file: PDF EDITORIALE
Dimensione 6.13 MB
Formato Adobe PDF
6.13 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1878289
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 12
  • ???jsp.display-item.citation.isi??? 12
social impact