First Cdc7 Kinase Inhibitors: Pyrrolopyridinones as Potent and Orally Active Antitumor Agents. 2. Lead Discovery

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• 作者：Maria Menichincheri ; Alberto Bargiotti ; Jens Berthelsen ; Jay A. Bertrand ; Roberto Bossi ; Antonella Ciavolella ; Alessandra Cirla ; Cinzia Cristiani ; Valter Croci ; Roberto D’ ; Alessio ; Marina Fasolin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：January 22, 2009
• 年：2009
• 卷：52
• 期：2
• 页码：293-307
• 全文大小：339K
• 年卷期：v.52,no.2(January 22, 2009)
• ISSN：1520-4804

文摘

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 K_i 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.