TY - JOUR
T1 - First Cdc7 kinase inhibitors
T2 - Pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery
AU - Menichincheri, Maria
AU - Bargiotti, Alberto
AU - Berthelsen, Jens
AU - Bertrand, Jay A.
AU - Bossi, Roberto
AU - Ciavolella, Antonella
AU - Cirla, Alessandra
AU - Cristiani, Cinzia
AU - Croci, Valter
AU - D'Alessio, Roberto
AU - Fasolini, Marina
AU - Fiorentini, Francesco
AU - Forte, Barbara
AU - Isacchi, Antonella
AU - Martina, Katia
AU - Molinari, Antonio
AU - Montagnoli, Alessia
AU - Orsini, Paolo
AU - Orzi, Fabrizio
AU - Pesenti, Enrico
AU - Pezzetta, Daniele
AU - Pillan, Antonio
AU - Poggesi, Italo
AU - Roletto, Fulvia
AU - Scolaro, Alessandra
AU - Tato, Marco
AU - Tibolla, Marcellino
AU - Valsasina, Barbara
AU - Varasi, Mario
AU - Volpi, Daniele
AU - Santocanale, Corrado
AU - Vanotti, Ermes
PY - 2009/1/22
Y1 - 2009/1/22
N2 - Cdc7 kinase is a key regulator of the S-phase of the cell cycle, known to promote the activation of DNA replication origins in eukaryotic organisms. Cdc7 inhibition can cause tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 inhibitors for the treatment of cancer. In this paper, we conclude the structure-activity relationships study of the 2-heteroaryl-pyrrolopyridinone class of compounds that display potent inhibitory activity against Cdc7 kinase. Furthermore, we also describe the discovery of 89S,[(S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoro-ethyl)-1,5,6,7- tetrahydropyrrolo[3,2-c]pyridin- 4-one], as a potent ATP mimetic inhibitor of Cdc7. Compound 89S has a Ki value of 0.5 nM, inhibits cell proliferation of different tumor cell lines with an IC50 in the submicromolar range, and exhibits in vivo tumor growth inhibition of 68% in the A2780 xenograft model.
AB - Cdc7 kinase is a key regulator of the S-phase of the cell cycle, known to promote the activation of DNA replication origins in eukaryotic organisms. Cdc7 inhibition can cause tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 inhibitors for the treatment of cancer. In this paper, we conclude the structure-activity relationships study of the 2-heteroaryl-pyrrolopyridinone class of compounds that display potent inhibitory activity against Cdc7 kinase. Furthermore, we also describe the discovery of 89S,[(S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoro-ethyl)-1,5,6,7- tetrahydropyrrolo[3,2-c]pyridin- 4-one], as a potent ATP mimetic inhibitor of Cdc7. Compound 89S has a Ki value of 0.5 nM, inhibits cell proliferation of different tumor cell lines with an IC50 in the submicromolar range, and exhibits in vivo tumor growth inhibition of 68% in the A2780 xenograft model.
UR - https://www.scopus.com/pages/publications/60549104083
U2 - 10.1021/jm800977q
DO - 10.1021/jm800977q
M3 - Article
SN - 0022-2623
VL - 52
SP - 293
EP - 307
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 2
ER -
