Research output per year
Research output per year
Maria Menichincheri, Alberto Bargiotti, Jens Berthelsen, Jay A. Bertrand, Roberto Bossi, Antonella Ciavolella, Alessandra Cirla, Cinzia Cristiani, Valter Croci, Roberto D'Alessio, Marina Fasolini, Francesco Fiorentini, Barbara Forte, Antonella Isacchi, Katia Martina, Antonio Molinari, Alessia Montagnoli, Paolo Orsini, Fabrizio Orzi, Enrico Pesenti
Research output: Contribution to journal › Article › peer-review
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.
Original language | English |
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Pages (from-to) | 293-307 |
Number of pages | 15 |
Journal | Journal of Medicinal Chemistry |
Volume | 52 |
Issue number | 2 |
Early online date | 30 Dec 2008 |
DOIs | |
Publication status | Published - 22 Jan 2009 |
Research output: Contribution to journal › Comment/debate › peer-review