Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding

Maria Menichincheri; Clara Albanese; Cristina Alli; Dario Ballinari; Alberto Bargiotti; Marina Caldarelli; Antonella Ciavolella; Alessandra Cirla; Maristella Colombo; Francesco Colotta; Valter Croci; Roberto Dalessio; Matteo Danello; Antonella Ermoli; Francesco Fiorentini; Barbara Forte; Arturo Galvani; Patrizia Giordano; Antonella Isacchi; Katia Martina; Antonio Molinari; Jürgen K. Moll; Alessia Montagnoli; Paolo Orsini; Fabrizio Orzi; Enrico Pesenti; Antonio Pillan; Fulvia Roletto; Alessandra Scolaro; Marco Tatò; Marcellino Tibolla; Barbara Valsasina; Mario Varasi; Paola Vianello; Daniele Volpi; Corrado Santocanale; Ermes Vanotti

doi:10.1021/jm100504d

Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding

Maria Menichincheri (Lead / Corresponding author), Clara Albanese, Cristina Alli, Dario Ballinari, Alberto Bargiotti, Marina Caldarelli, Antonella Ciavolella, Alessandra Cirla, Maristella Colombo, Francesco Colotta, Valter Croci, Roberto Dalessio, Matteo Danello, Antonella Ermoli, Francesco Fiorentini, Barbara Forte, Arturo Galvani, Patrizia Giordano, Antonella Isacchi, Katia MartinaAntonio Molinari, Jürgen K. Moll, Alessia Montagnoli, Paolo Orsini, Fabrizio Orzi, Enrico Pesenti, Antonio Pillan, Fulvia Roletto, Alessandra Scolaro, Marco Tatò, Marcellino Tibolla, Barbara Valsasina, Mario Varasi, Paola Vianello, Daniele Volpi, Corrado Santocanale, Ermes Vanotti

Drug Discovery Unit

Research output: Contribution to journal › Article › peer-review

61 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	7296-7315
Number of pages	20
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	20
Early online date	27 Sept 2010
DOIs	https://doi.org/10.1021/jm100504d
Publication status	Published - 28 Oct 2010

Keywords

Amides
Inhibition
Peptides and proteins
Pyrroles
Reaction products

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/jm100504d

Cite this

Menichincheri, M., Albanese, C., Alli, C., Ballinari, D., Bargiotti, A., Caldarelli, M., Ciavolella, A., Cirla, A., Colombo, M., Colotta, F., Croci, V., Dalessio, R., Danello, M., Ermoli, A., Fiorentini, F., Forte, B., Galvani, A., Giordano, P., Isacchi, A., ... Vanotti, E. (2010). Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding. Journal of Medicinal Chemistry, 53(20), 7296-7315. https://doi.org/10.1021/jm100504d

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title = "Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding",

abstract = "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.",

keywords = "Amides, Inhibition, Peptides and proteins, Pyrroles, Reaction products",

author = "Maria Menichincheri and Clara Albanese and Cristina Alli and Dario Ballinari and Alberto Bargiotti and Marina Caldarelli and Antonella Ciavolella and Alessandra Cirla and Maristella Colombo and Francesco Colotta and Valter Croci and Roberto Dalessio and Matteo Danello and Antonella Ermoli and Francesco Fiorentini and Barbara Forte and Arturo Galvani and Patrizia Giordano and Antonella Isacchi and Katia Martina and Antonio Molinari and Moll, {J{\"u}rgen K.} and Alessia Montagnoli and Paolo Orsini and Fabrizio Orzi and Enrico Pesenti and Antonio Pillan and Fulvia Roletto and Alessandra Scolaro and Marco Tat{\`o} and Marcellino Tibolla and Barbara Valsasina and Mario Varasi and Paola Vianello and Daniele Volpi and Corrado Santocanale and Ermes Vanotti",

note = "Copyright: {\textcopyright} 2010 American Chemical Society.",

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Menichincheri, M, Albanese, C, Alli, C, Ballinari, D, Bargiotti, A, Caldarelli, M, Ciavolella, A, Cirla, A, Colombo, M, Colotta, F, Croci, V, Dalessio, R, Danello, M, Ermoli, A, Fiorentini, F, Forte, B, Galvani, A, Giordano, P, Isacchi, A, Martina, K, Molinari, A, Moll, JK, Montagnoli, A, Orsini, P, Orzi, F, Pesenti, E, Pillan, A, Roletto, F, Scolaro, A, Tatò, M, Tibolla, M, Valsasina, B, Varasi, M, Vianello, P, Volpi, D, Santocanale, C & Vanotti, E 2010, 'Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding', Journal of Medicinal Chemistry, vol. 53, no. 20, pp. 7296-7315. https://doi.org/10.1021/jm100504d

TY - JOUR

T1 - Cdc7 kinase inhibitors

T2 - 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding

AU - Menichincheri, Maria

AU - Albanese, Clara

AU - Alli, Cristina

AU - Ballinari, Dario

AU - Bargiotti, Alberto

AU - Caldarelli, Marina

AU - Ciavolella, Antonella

AU - Cirla, Alessandra

AU - Colombo, Maristella

AU - Colotta, Francesco

AU - Croci, Valter

AU - Dalessio, Roberto

AU - Danello, Matteo

AU - Ermoli, Antonella

AU - Fiorentini, Francesco

AU - Forte, Barbara

AU - Galvani, Arturo

AU - Giordano, Patrizia

AU - Isacchi, Antonella

AU - Martina, Katia

AU - Molinari, Antonio

AU - Moll, Jürgen K.

AU - Montagnoli, Alessia

AU - Orsini, Paolo

AU - Orzi, Fabrizio

AU - Pesenti, Enrico

AU - Pillan, Antonio

AU - Roletto, Fulvia

AU - Scolaro, Alessandra

AU - Tatò, Marco

AU - Tibolla, Marcellino

AU - Valsasina, Barbara

AU - Varasi, Mario

AU - Vianello, Paola

AU - Volpi, Daniele

AU - Santocanale, Corrado

AU - Vanotti, Ermes

PY - 2010/10/28

Y1 - 2010/10/28

N2 - 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.

AB - 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.

KW - Amides

KW - Inhibition

KW - Peptides and proteins

KW - Pyrroles

KW - Reaction products

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U2 - 10.1021/jm100504d

DO - 10.1021/jm100504d

M3 - Article

C2 - 20873740

AN - SCOPUS:77958498566

SN - 0022-2623

VL - 53

SP - 7296

EP - 7315

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 20

ER -

Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding

Abstract

Keywords

ASJC Scopus subject areas

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