3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding

Paolo Pevarello; Maria Gabriella Brasca; Raffaella Amici; Paolo Orsini; Gabriella Traquandi; Luca Corti; Claudia Piutti; Pietro Sansonna; Manuela Villa; Betsy S. Pierce; Maurizio Pulici; Patrizia Giordano; Katia Martina; Edward L. Fritzen; Richard A. Nugent; Elena Casale; Alexander Cameron; Marina Ciomei; Fulvia Roletto; Antonella Isacchi; GianPaolo Fogliatto; Enrico Pesenti; Wilma Pastori; Aurelio Marsiglio; Karen L. Leach; Paula M. Clare; Francesco Fiorentini; Mario Varasi; Anna Vulpetti; Martha A. Warpehoski

doi:10.1021/jm031145u

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding

Paolo Pevarello, Maria Gabriella Brasca, Raffaella Amici, Paolo Orsini, Gabriella Traquandi, Luca Corti, Claudia Piutti, Pietro Sansonna, Manuela Villa, Betsy S. Pierce, Maurizio Pulici, Patrizia Giordano, Katia Martina, Edward L. Fritzen, Richard A. Nugent, Elena Casale, Alexander Cameron, Marina Ciomei, Fulvia Roletto, Antonella IsacchiGianPaolo Fogliatto, Enrico Pesenti, Wilma Pastori, Aurelio Marsiglio, Karen L. Leach, Paula M. Clare, Francesco Fiorentini, Mario Varasi, Anna Vulpetti, Martha A. Warpehoski

Istituto Europeo di Oncologia

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

Abstract

Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC₅₀ = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.

Original language	English
Pages (from-to)	3367-3380
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	47
Issue number	13
DOIs	https://doi.org/10.1021/jm031145u
Publication status	Published - Jun 17 2004

ASJC Scopus subject areas

Organic Chemistry

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10.1021/jm031145u

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Pevarello, P., Brasca, M. G., Amici, R., Orsini, P., Traquandi, G., Corti, L., Piutti, C., Sansonna, P., Villa, M., Pierce, B. S., Pulici, M., Giordano, P., Martina, K., Fritzen, E. L., Nugent, R. A., Casale, E., Cameron, A., Ciomei, M., Roletto, F., ... Warpehoski, M. A. (2004). 3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding. Journal of Medicinal Chemistry, 47(13), 3367-3380. https://doi.org/10.1021/jm031145u

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding. / Pevarello, Paolo; Brasca, Maria Gabriella; Amici, Raffaella; Orsini, Paolo; Traquandi, Gabriella; Corti, Luca; Piutti, Claudia; Sansonna, Pietro; Villa, Manuela; Pierce, Betsy S.; Pulici, Maurizio; Giordano, Patrizia; Martina, Katia; Fritzen, Edward L.; Nugent, Richard A.; Casale, Elena; Cameron, Alexander; Ciomei, Marina; Roletto, Fulvia; Isacchi, Antonella; Fogliatto, GianPaolo; Pesenti, Enrico; Pastori, Wilma; Marsiglio, Aurelio; Leach, Karen L.; Clare, Paula M.; Fiorentini, Francesco; Varasi, Mario; Vulpetti, Anna; Warpehoski, Martha A.

In: Journal of Medicinal Chemistry, Vol. 47, No. 13, 17.06.2004, p. 3367-3380.

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

Pevarello, P, Brasca, MG, Amici, R, Orsini, P, Traquandi, G, Corti, L, Piutti, C, Sansonna, P, Villa, M, Pierce, BS, Pulici, M, Giordano, P, Martina, K, Fritzen, EL, Nugent, RA, Casale, E, Cameron, A, Ciomei, M, Roletto, F, Isacchi, A, Fogliatto, G, Pesenti, E, Pastori, W, Marsiglio, A, Leach, KL, Clare, PM, Fiorentini, F, Varasi, M, Vulpetti, A & Warpehoski, MA 2004, '3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding', Journal of Medicinal Chemistry, vol. 47, no. 13, pp. 3367-3380. https://doi.org/10.1021/jm031145u

Pevarello, Paolo ; Brasca, Maria Gabriella ; Amici, Raffaella ; Orsini, Paolo ; Traquandi, Gabriella ; Corti, Luca ; Piutti, Claudia ; Sansonna, Pietro ; Villa, Manuela ; Pierce, Betsy S. ; Pulici, Maurizio ; Giordano, Patrizia ; Martina, Katia ; Fritzen, Edward L. ; Nugent, Richard A. ; Casale, Elena ; Cameron, Alexander ; Ciomei, Marina ; Roletto, Fulvia ; Isacchi, Antonella ; Fogliatto, GianPaolo ; Pesenti, Enrico ; Pastori, Wilma ; Marsiglio, Aurelio ; Leach, Karen L. ; Clare, Paula M. ; Fiorentini, Francesco ; Varasi, Mario ; Vulpetti, Anna ; Warpehoski, Martha A. / 3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 13. pp. 3367-3380.

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abstract = "Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.",

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AU - Pevarello, Paolo

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AU - Orsini, Paolo

AU - Traquandi, Gabriella

AU - Corti, Luca

AU - Piutti, Claudia

AU - Sansonna, Pietro

AU - Villa, Manuela

AU - Pierce, Betsy S.

AU - Pulici, Maurizio

AU - Giordano, Patrizia

AU - Martina, Katia

AU - Fritzen, Edward L.

AU - Nugent, Richard A.

AU - Casale, Elena

AU - Cameron, Alexander

AU - Ciomei, Marina

AU - Roletto, Fulvia

AU - Isacchi, Antonella

AU - Fogliatto, GianPaolo

AU - Pesenti, Enrico

AU - Pastori, Wilma

AU - Marsiglio, Aurelio

AU - Leach, Karen L.

AU - Clare, Paula M.

AU - Fiorentini, Francesco

AU - Varasi, Mario

AU - Vulpetti, Anna

AU - Warpehoski, Martha A.

PY - 2004/6/17

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