Vanotti Ermes, Amici Raffaella, Bargiotti Alberto, Berthelsen Jens, Bosotti Roberta, Ciavolella Antonella, Cirla Alessandra, Cristiani Cinzia, D'Alessio Roberto, Forte Barbara, Isacchi Antonella, Martina Katia, Menichincheri Maria, Molinari Antonio, Montagnoli Alessia, Orsini Paolo, Pillan Antonio, Roletto Fulvia, Scolaro Alessandra, Tibolla Marcellino, Valsasina Barbara, Varasi Mario, Volpi Daniele, Santocanale Corrado
Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, Milano, Italy.
J Med Chem. 2008 Feb 14;51(3):487-501. doi: 10.1021/jm700956r. Epub 2008 Jan 18.
Cdc7 kinase is an essential protein that promotes DNA replication in eukaryotic organisms. Genetic evidence indicates that Cdc7 inhibition can cause selective tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 small-molecule inhibitors for the treatment of cancers. In this paper, the synthesis and structure-activity relationships of 2-heteroaryl-pyrrolopyridinones, the first potent Cdc7 kinase inhibitors, are described. Starting from 2-pyridin-4-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one, progress toward a simple scaffold, tailored for Cdc7 inhibition, is reported.
细胞周期蛋白依赖性激酶7（Cdc7）是一种在真核生物中促进DNA复制的必需蛋白。遗传学证据表明，抑制Cdc7可以以一种不依赖p53的方式导致选择性肿瘤细胞死亡，这为开发用于治疗癌症的Cdc7小分子抑制剂提供了理论依据。本文描述了首个强效Cdc7激酶抑制剂2-杂芳基-吡咯并吡啶酮的合成及其构效关系。报道了从2-吡啶-4-基-1,5,6,7-四氢-吡咯并[3,2-c]吡啶-4-酮开始，朝着为抑制Cdc7量身定制的简单骨架的进展情况。
