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 Pesenti; Daniele Pezzetta; Antonio Pillan; Italo Poggesi; Fulvia Roletto; Alessandra Scolaro; Marco Tato; Marcellino Tibolla; Barbara Valsasina; Mario Varasi; Daniele Volpi; Corrado Santocanale; Ermes Vanotti

doi:10.1021/jm800977q

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 Pesenti

Daniele Pezzetta, Antonio Pillan, Italo Poggesi, Fulvia Roletto, Alessandra Scolaro, Marco Tato, Marcellino Tibolla, Barbara Valsasina, Mario Varasi, Daniele Volpi, Corrado Santocanale, Ermes Vanotti

Oncology
University of Turin
GlaxoSmithKline SpA
University of Galway
Genextra Group S.p.A

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

67 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 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.

Original language	English
Pages (from-to)	293-307
Number of pages	15
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	2
DOIs	https://doi.org/10.1021/jm800977q
Publication status	Published - 22 Jan 2009
Externally published	Yes

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SDG 3 Good Health and Well-being

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10.1021/jm800977q

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Menichincheri, M., Bargiotti, A., Berthelsen, J., Bertrand, J. A., 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., ... 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

@article{6c612f323a8142d5898ea22e53e3c8b7,

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

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.",

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

year = "2009",

month = jan,

day = "22",

doi = "10.1021/jm800977q",

language = "English",

volume = "52",

pages = "293--307",

journal = "Journal of Medicinal Chemistry",

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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

TY - JOUR

T1 - First Cdc7 kinase inhibitors

T2 - Pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery

AU - Menichincheri, Maria

AU - Bargiotti, Alberto

AU - Berthelsen, Jens

AU - Bertrand, Jay A.

AU - Bossi, Roberto

AU - Ciavolella, Antonella

AU - Cirla, Alessandra

AU - Cristiani, Cinzia

AU - Croci, Valter

AU - D'Alessio, Roberto

AU - Fasolini, Marina

AU - Fiorentini, Francesco

AU - Forte, Barbara

AU - Isacchi, Antonella

AU - Martina, Katia

AU - Molinari, Antonio

AU - Montagnoli, Alessia

AU - Orsini, Paolo

AU - Orzi, Fabrizio

AU - Pesenti, Enrico

AU - Pezzetta, Daniele

AU - Pillan, Antonio

AU - Poggesi, Italo

AU - Roletto, Fulvia

AU - Scolaro, Alessandra

AU - Tato, Marco

AU - Tibolla, Marcellino

AU - Valsasina, Barbara

AU - Varasi, Mario

AU - Volpi, Daniele

AU - Santocanale, Corrado

AU - Vanotti, Ermes

PY - 2009/1/22

Y1 - 2009/1/22

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/60549104083

U2 - 10.1021/jm800977q

DO - 10.1021/jm800977q

M3 - Article

SN - 0022-2623

VL - 52

SP - 293

EP - 307

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 2

ER -

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

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