First Cdc7 kinase inhibitors: Pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery

Maria Menichincheri, Alberto Bargiotti, Jens Berthelsen, Jay A. Bertrand, Roberto Bossi, Antonella Ciavolella, Alessandra Cirla, Cinzia Cristiani, Valter Croci, Roberto D'Alessio, Marina Fasolini, Francesco Fiorentini, Barbara Forte, Antonella Isacchi, Katia Martina, Antonio Molinari, Alessia Montagnoli, Paolo Orsini, Fabrizio Orzi, Enrico PesentiDaniele Pezzetta, Antonio Pillan, Italo Poggesi, Fulvia Roletto, Alessandra Scolaro, Marco Tato, Marcellino Tibolla, Barbara Valsasina, Mario Varasi, Daniele Volpi, Corrado Santocanale, Ermes Vanotti

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

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 Ki 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.

Original languageEnglish
Pages (from-to)293-307
Number of pages15
JournalJournal of Medicinal Chemistry
Volume52
Issue number2
DOIs
Publication statusPublished - Jan 22 2009

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Antineoplastic Agents
Phosphotransferases
Neoplasms
Replication Origin
Structure-Activity Relationship
Tumor Cell Line
DNA Replication
S Phase
Heterografts
Inhibitory Concentration 50
Cell Cycle
Cell Death
Adenosine Triphosphate
Cell Proliferation
Growth
Lead

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Menichincheri, M., Bargiotti, A., Berthelsen, J., Bertrand, J. A., Bossi, R., Ciavolella, A., ... Vanotti, E. (2009). First Cdc7 kinase inhibitors: Pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. Journal of Medicinal Chemistry, 52(2), 293-307. https://doi.org/10.1021/jm800977q

First Cdc7 kinase inhibitors : Pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. / Menichincheri, Maria; Bargiotti, Alberto; Berthelsen, Jens; Bertrand, Jay A.; Bossi, Roberto; Ciavolella, Antonella; Cirla, Alessandra; Cristiani, Cinzia; Croci, Valter; D'Alessio, Roberto; Fasolini, Marina; Fiorentini, Francesco; Forte, Barbara; Isacchi, Antonella; Martina, Katia; Molinari, Antonio; Montagnoli, Alessia; Orsini, Paolo; Orzi, Fabrizio; Pesenti, Enrico; Pezzetta, Daniele; Pillan, Antonio; Poggesi, Italo; Roletto, Fulvia; Scolaro, Alessandra; Tato, Marco; Tibolla, Marcellino; Valsasina, Barbara; Varasi, Mario; Volpi, Daniele; Santocanale, Corrado; Vanotti, Ermes.

In: Journal of Medicinal Chemistry, Vol. 52, No. 2, 22.01.2009, p. 293-307.

Research output: Contribution to journalArticle

Menichincheri, M, Bargiotti, A, Berthelsen, J, Bertrand, JA, Bossi, R, Ciavolella, A, Cirla, A, Cristiani, C, Croci, V, D'Alessio, R, Fasolini, M, Fiorentini, F, Forte, B, Isacchi, A, Martina, K, Molinari, A, Montagnoli, A, Orsini, P, Orzi, F, Pesenti, E, Pezzetta, D, Pillan, A, Poggesi, I, Roletto, F, Scolaro, A, Tato, M, Tibolla, M, Valsasina, B, Varasi, M, Volpi, D, Santocanale, C & Vanotti, E 2009, 'First Cdc7 kinase inhibitors: Pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery', Journal of Medicinal Chemistry, vol. 52, no. 2, pp. 293-307. https://doi.org/10.1021/jm800977q
Menichincheri M, Bargiotti A, Berthelsen J, Bertrand JA, Bossi R, Ciavolella A et al. First Cdc7 kinase inhibitors: Pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. Journal of Medicinal Chemistry. 2009 Jan 22;52(2):293-307. https://doi.org/10.1021/jm800977q
Menichincheri, Maria ; Bargiotti, Alberto ; Berthelsen, Jens ; Bertrand, Jay A. ; Bossi, Roberto ; Ciavolella, Antonella ; Cirla, Alessandra ; Cristiani, Cinzia ; Croci, Valter ; D'Alessio, Roberto ; Fasolini, Marina ; Fiorentini, Francesco ; Forte, Barbara ; Isacchi, Antonella ; Martina, Katia ; Molinari, Antonio ; Montagnoli, Alessia ; Orsini, Paolo ; Orzi, Fabrizio ; Pesenti, Enrico ; Pezzetta, Daniele ; Pillan, Antonio ; Poggesi, Italo ; Roletto, Fulvia ; Scolaro, Alessandra ; Tato, Marco ; Tibolla, Marcellino ; Valsasina, Barbara ; Varasi, Mario ; Volpi, Daniele ; Santocanale, Corrado ; Vanotti, Ermes. / First Cdc7 kinase inhibitors : Pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 2. pp. 293-307.
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