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

被引：59

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

共 30 条

[1] DNA replication in eukaryotic cells [J].

Bell, SP ;

Dutta, A .

ANNUAL REVIEW OF BIOCHEMISTRY, 2002, 71 :333-374

[2] A COMPARISON OF ACID LABILE LINKAGE AGENTS FOR THE SYNTHESIS OF PEPTIDE C-TERMINAL AMIDES [J].

BERNATOWICZ, MS ;

DANIELS, SB ;

KOSTER, H .

TETRAHEDRON LETTERS, 1989, 30 (35) :4645-4648

[3] Cdc7-Dbf4 kinase overexpression in multiple cancers and tumor cell lines is correlated with p53 inactivation [J].

Bonte, Dorine ;

Lindvall, Charlotta ;

Liu, Honyu ;

Dykema, Karl ;

Furge, Kyle ;

Weinreich, Michael .

NEOPLASIA, 2008, 10 (09) :920-U31

[4]

BRAM G, 1964, B SOC CHIM FR, P945

[5] C-ACYLATION UNDER VIRTUALLY NEUTRAL CONDITIONS [J].

BROOKS, DW ;

LU, LDL ;

MASAMUNE, S .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION IN ENGLISH, 1979, 18 (01) :72-74

[6]

Chabner B.A., 2001, The Pharmacological Basis of Therapeutics, P1389

[7] A fully automated method for accurate mass determination using high-performance liquid chromatography with a quadrupole/orthogonal acceleration time-of-flight mass spectrometer [J].

Colombo, M ;

Sirtori, FR ;

Rizzo, V .

RAPID COMMUNICATIONS IN MASS SPECTROMETRY, 2004, 18 (04) :511-517

[8] Cell Division Cycle 7 Kinase Inhibitors: 1H-Pyrrolo[2,3-b]pyridines, Synthesis and Structure - Activity Relationships [J].

Ermoli, Antonella ;

Bargiotti, Alberto ;

Brasca, Maria Gabriella ;

Ciavolella, Antonella ;

Colombo, Nicoletta ;

Fachin, Gabriele ;

Isacchi, Antonella ;

Menichincheri, Maria ;

Molinari, Antonio ;

Montagnoli, Alessia ;

Pillan, Antonio ;

Rainoldi, Sonia ;

Sirtori, Federico Riccardi ;

Sola, Francesco ;

Thieffine, Sandrine ;

Tibolla, Marcellino ;

Valsasina, Barbara ;

Volpi, Daniele ;

Santocanale, Corrado ;

Vanotti, Ermes .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (14) :4380-4390

[9] AN EFFICIENT SYNTHESIS OF 2-CHLORO-3-CARBOETHOXY OR 2-CHLORO-3-CYANO 4,5-DISUBSTITUTED AND 5-SUBSTITUTED PYRROLES [J].

FOLEY, LH .

TETRAHEDRON LETTERS, 1994, 35 (33) :5989-5992

[10] Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication [J].

Jiang, W ;

McDonald, D ;

Hope, TJ ;

Hunter, T .

EMBO JOURNAL, 1999, 18 (20) :5703-5713

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