Cdc7 Kinase Inhibitors: 5-Heteroaryl-3-Carboxamido-2-Aryl Pyrroles as Potential Antitumor Agents. 1. Lead Finding

被引：61

作者：

Menichincheri, Maria ^{[1
]}

Albanese, Clara ^{[1
]}

Alli, Cristina ^{[1
]}

Ballinari, Dario ^{[1
]}

Bargiotti, Alberto ^{[1
]}

Caldarelli, Marina ^{[1
]}

Ciavolella, Antonella ^{[1
]}

Cirla, Alessandra ^{[1
]}

Colombo, Maristella ^{[1
]}

Colotta, Francesco ^{[1
]}

Croci, Valter ^{[1
]}

D'Alessio, Roberto ^{[1
]}

D'Anello, Matteo ^{[1
]}

Ermoti, Antonella ^{[1
]}

Fiorentini, Francesco ^{[2
]}

Forte, Barbara ^{[1
]}

Galvani, Arturo ^{[1
]}

Giordano, Patrizia ^{[1
]}

Isacchi, Antonella ^{[1
]}

Martina, Katia ^{[1
]}

Molinari, Antonio ^{[2
]}

Moll, Juegen K. ^{[1
]}

Montagnoli, Alessia ^{[1
]}

Orsini, Paolo ^{[1
]}

Orzi, Fabrizio ^{[1
]}

Pesenti, Enrico ^{[1
]}

Pillan, Antonio ^{[1
]}

Roletto, Fulvia ^{[1
]}

Scolaro, Alessandra ^{[1
]}

Tato, Marco ^{[1
]}

Tibolla, Marcellino ^{[1
]}

Valsasina, Barbara ^{[1
]}

Varasi, Mario ^{[1
]}

Vianello, Paola ^{[1
]}

Volpi, Daniele ^{[1
]}

Santocanale, Corrado ^{[1
]}

Vanottit, Ermes ^{[1
]}

机构：

[1] Nerviano Med Sci Srl, Business Unit Oncol, I-20014 Nerviano, MI, Italy

[2] Accelera Srl, I-20014 Nerviano, MI, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 20期

关键词：

DNA-REPLICATION; EFFICIENT SYNTHESIS; INITIATION; PYRROLOPYRIDINONES; PHOSPHORYLATION; MCM2;

D O I：

10.1021/jm100504d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considered a potential target for anticancer therapy. We previously reported that pyrrolopyridinones (e.g., 1) are potent and selective inhibitors of Cdc7 kinase, with good cellular potency and in vitro ADME properties but with suboptimal pharmacokinetic profiles. Here we report on a new chemical class of 5-heteroaryl-3-carboxamido-2-substituted pyrroles (1A) that offers advantages of chemistry diversification and synthetic simplification. This work led to the identification of compound 18, with biochemical data and ADME profile similar to those of compound 1 but characterized by superior efficacy in an in vivo model. Derivative 18 represents a new lead compound worthy of further investigation toward the ultimate goal of identifying a clinical candidate.

引用

页码：7296 / 7315

页数：20

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