NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor

Italo Beria; Roberto T. Bossi; Maria Gabriella Brasca; Michele Caruso; Walter Ceccarelli; Gabriele Fachin; Marina Fasolini; Barbara Forte; Francesco Fiorentini; Enrico Pesenti; Daniele Pezzetta; Helena Posteri; Alessandra Scolaro; Stefania Re Depaolini; Barbara Valsasina

doi:10.1016/j.bmcl.2011.03.054

NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor

Italo Beria (Lead / Corresponding author)
, Roberto T. Bossi
, Maria Gabriella Brasca
, Michele Caruso
, Walter Ceccarelli
, Gabriele Fachin
, Marina Fasolini
, Barbara Forte
, Francesco Fiorentini
, Enrico Pesenti
, Daniele Pezzetta
, Helena Posteri
, Alessandra Scolaro
, Stefania Re Depaolini
, Barbara Valsasina

Drug Discovery Unit

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

104 Citations (Scopus)

Abstract

As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order to understand the source of PLK1 selectivity, we determined the crystal structure of PLK1 with NMS-P937. The compound was active in vivo in HCT116 xenograft model after oral administration and is presently in Phase I clinical trials evaluation.

Original language	English
Pages (from-to)	2969-2974
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	10
Early online date	21 Mar 2011
DOIs	https://doi.org/10.1016/j.bmcl.2011.03.054
Publication status	Published - 15 May 2011

Keywords

In vivo activity
Kinase inhibitor
Phase I clinical trials
PLK1
Polo-like kinase

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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Beria, I., Bossi, R. T., Brasca, M. G., Caruso, M., Ceccarelli, W., Fachin, G., Fasolini, M., Forte, B., Fiorentini, F., Pesenti, E., Pezzetta, D., Posteri, H., Scolaro, A., Depaolini, S. R., & Valsasina, B. (2011). NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor. Bioorganic and Medicinal Chemistry Letters, 21(10), 2969-2974. https://doi.org/10.1016/j.bmcl.2011.03.054

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abstract = "As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order to understand the source of PLK1 selectivity, we determined the crystal structure of PLK1 with NMS-P937. The compound was active in vivo in HCT116 xenograft model after oral administration and is presently in Phase I clinical trials evaluation.",

keywords = "In vivo activity, Kinase inhibitor, Phase I clinical trials, PLK1, Polo-like kinase",

author = "Italo Beria and Bossi, \{Roberto T.\} and Brasca, \{Maria Gabriella\} and Michele Caruso and Walter Ceccarelli and Gabriele Fachin and Marina Fasolini and Barbara Forte and Francesco Fiorentini and Enrico Pesenti and Daniele Pezzetta and Helena Posteri and Alessandra Scolaro and Depaolini, \{Stefania Re\} and Barbara Valsasina",

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language = "English",

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Beria, I, Bossi, RT, Brasca, MG, Caruso, M, Ceccarelli, W, Fachin, G, Fasolini, M, Forte, B, Fiorentini, F, Pesenti, E, Pezzetta, D, Posteri, H, Scolaro, A, Depaolini, SR & Valsasina, B 2011, 'NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 10, pp. 2969-2974. https://doi.org/10.1016/j.bmcl.2011.03.054

NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor. / Beria, Italo (Lead / Corresponding author); Bossi, Roberto T.; Brasca, Maria Gabriella et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 10, 15.05.2011, p. 2969-2974.

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

TY - JOUR

T1 - NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor

AU - Beria, Italo

AU - Bossi, Roberto T.

AU - Brasca, Maria Gabriella

AU - Caruso, Michele

AU - Ceccarelli, Walter

AU - Fachin, Gabriele

AU - Fasolini, Marina

AU - Forte, Barbara

AU - Fiorentini, Francesco

AU - Pesenti, Enrico

AU - Pezzetta, Daniele

AU - Posteri, Helena

AU - Scolaro, Alessandra

AU - Depaolini, Stefania Re

AU - Valsasina, Barbara

PY - 2011/5/15

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KW - In vivo activity

KW - Kinase inhibitor

KW - Phase I clinical trials

KW - PLK1

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ER -

NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor

Abstract

Keywords

ASJC Scopus subject areas

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