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

被引：62

作者：

Menichincheri, Maria ^{[1
]}

Bargiotti, Alberto ^{[1
]}

Berthelsen, Jens ^{[1
]}

Bertrand, Jay A. ^{[1
]}

Bossi, Roberto ^{[1
]}

Ciavolella, Antonella ^{[1
]}

Cirla, Alessandra ^{[1
]}

Cristiani, Cinzia ^{[1
]}

Croci, Valter ^{[1
]}

D'Alessio, Roberto ^{[1
]}

Fasolini, Marina ^{[1
]}

Fiorentini, Francesco ^{[1
]}

Forte, Barbara ^{[1
]}

Isacchi, Antonella ^{[1
]}

Martina, Katia ^{[2
]}

Molinari, Antonio ^{[2
]}

Montagnoli, Alessia ^{[1
]}

Orsini, Paolo ^{[1
]}

Orzi, Fabrizio ^{[1
]}

Pesenti, Enrico ^{[1
]}

Pezzetta, Daniele ^{[1
]}

Pillan, Antonio ^{[1
]}

Poggesi, Italo ^{[3
]}

Roletto, Fulvia ^{[1
]}

Scolaro, Alessandra ^{[1
]}

Tato, Marco ^{[1
]}

Tibolla, Marcellino ^{[1
]}

Valsasina, Barbara ^{[1
]}

Varasi, Mario ^{[4
]}

Volpi, Daniele ^{[1
]}

Santocanale, Corrado ^{[1
,5
]}

Vanotti, Ermes ^{[1
]}

机构：

[1] Nerviano Med Sci Srl, I-20014 Milan, Italy

[2] Univ Turin, Dipartimento Chim IFM, Turin, Italy

[3] GlaxoSmithKline SpA, Verona, Italy

[4] Genextra Grp SpA, Milan, Italy

[5] Natl Univ Ireland, Natl Ctr Biomed Engn & Sci, Galway, Ireland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 02期

关键词：

HUMAN CDC7-RELATED KINASE; IN-VITRO PHOSPHORYLATION; DNA-REPLICATION; HUMAN HOMOLOG; PROTEIN; CELLS; IDENTIFICATION; INITIATION; COMPLEX; GROWTH;

D O I：

10.1021/jm800977q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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, 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-tetrahydropyrrolol[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.

引用

页码：293 / 307

页数：15

共 37 条

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