کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1361940 | 981475 | 2011 | 6 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor](/preview/png/1361940.png)
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.
Lead optimization work on the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline series led to identification of NMS-P937. Crystal structure of NMS-P937 with PLK1 was obtained and discussed. NMS-P937 is a potent, selective and orally available PLK1 inhibitor that is presently in Phase I clinical trials.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 21, Issue 10, 15 May 2011, Pages 2969–2974