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

被引：94

作者：

Beria, Italo ^{[1
]}

Bossi, Roberto T. ^{[1
]}

Brasca, Maria Gabriella ^{[1
]}

Caruso, Michele ^{[1
]}

Ceccarelli, Walter ^{[1
]}

Fachin, Gabriele ^{[1
]}

Fasolini, Marina ^{[1
]}

Forte, Barbara ^{[1
]}

Fiorentini, Francesco ^{[2
]}

Pesenti, Enrico ^{[1
]}

Pezzetta, Daniele ^{[2
]}

Posteri, Helena ^{[1
]}

Scolaro, Alessandra ^{[1
]}

Depaolini, Stefania Re ^{[1
]}

Valsasina, Barbara ^{[1
]}

机构：

[1] Nerviano Med Sci Srl, Business Unit Oncol, I-20014 Nerviano, MI, Italy

[2] Accelera Srl, I-20014 Nerviano, MI, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 10期

关键词：

PLK1; Polo-like kinase; Kinase inhibitor; In vivo activity; Phase I clinical trials; CANCER; BINDING; PROTEIN; PLK1;

D O I：

10.1016/j.bmcl.2011.03.054

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：2969 / 2974

页数：6

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