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作者 |
Menichincheri, Maria;Bargiotti, Alberto;Berthelsen, Jens;Bertrand, Jay A.;Bossi, Roberto;Ciavolella, Antonella;Cirla, Alessandra;Cristiani, Cinzia;Croci, Valter;D'Alessio, Roberto;Fasolini, Marina;Fiorentini, Francesco;Forte, Barbara;Isacchi, Antonella;Ma |
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[摘要]：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, the structure-activity relationships study of the 2-heteroarylpyrrolopyridinones I (R1 = 4-pyridyl, 2-amino-4-pyrimidyl; R2 = H, R3 = Me, Et, cyclobutyl, FCH2CH2, Ph, etc.; R2 = Me, i-Pr, cyclopropyl, i-Bu, etc., R3 = H) that display potent inhibitory activity against Cdc7 kinase is presented. Furthermore, the discovery of (S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoroethyl)-1,5,6,7-tetrahydropyrrolo[ 3,2-c]pyridin-4-one II, a potent ATP mimetic inhibitor of Cdc7, is described. Compd. II 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. |
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