Synthesis and Biological Evaluation of Pyrazolo[1,5-a]pyrimidine Compounds as Potent and Selective Pim-1 Inhibitors

被引：51

作者：

Xu, Yong ^{[1
]}

Brenning, Benjamin G. ^{[1
]}

Kultgen, Steven G. ^{[1
]}

Foulks, Jason M. ^{[1
]}

Clifford, Adrianne ^{[1
]}

Lai, Shuping ^{[1
]}

Chan, Ashley ^{[1
]}

Merx, Shannon ^{[1
]}

McCullar, Michael V. ^{[1
]}

Kanner, Steven B. ^{[1
]}

Ho, Koc-Kan ^{[1
]}

机构：

[1] Astex Pharmaceut Inc, Dublin, CA 94568 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 01期

关键词：

Pyrazolo[1,5-a]pyrimidine; Pim-1; inhibitor; BAD phosphorylation; 2-dimensional colony formation; hERG inhibition; kinase selectivity; MANTLE CELL LYMPHOMA; KINASES; DISCOVERY; SGI-1776; TARGETS; DESIGN; CANCER;

D O I：

10.1021/ml500300c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Pim-1 has emerged as an attractive target for developing therapeutic agents for treating disorders involving abnormal cell growth, especially cancers. Herein we present lead optimization, chemical synthesis and biological evaluation of pyrazolo[1,5-a]pyrimidine compounds as potent and selective inhibitors of Pim-1 starting from a hit from virtual screening. These pyrazolo[1,5-a]pyrimidine compounds strongly inhibited Pim-1 and Flt-3 kinases. Selected compounds suppressed both the phosphorylation of BAD protein in a cell-based assay and 2-dimensional colony formation in a clonogenic cell survival assay at submicromolar potency, suggesting that cellular activity was mediated through inhibition of Pim-1. Moreover, these Pim-1 inhibitors did not show significant hERG inhibition at 30 mu M concentration. The lead compound proved to be highly selective against a panel of 119 oncogenic kinases, indicating it had an improved safety profile compared with the first generation Pim-1 inhibitor SGI-1776.

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页码：63 / 67

页数：5

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