Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design

被引：57

作者：

Wang, Xiaojing ^{[1
]}

Magnuson, Steven ^{[1
]}

Pastor, Rich ^{[1
]}

Fan, Eric ^{[2
]}

Hu, Huiyong ^{[1
]}

Tsui, Vickie ^{[1
]}

Deng, Wei ^{[3
]}

Murray, Jeremy ^{[1
]}

Steffek, Micah ^{[4
]}

Wallweber, Heidi ^{[1
]}

Moffat, John ^{[1
]}

Drummond, Jason ^{[1
]}

Chan, Grace ^{[1
]}

Harstad, Eric ^{[1
]}

Ebens, Allen J. ^{[1
]}

机构：

[1] Genentech Inc, San Francisco, CA 94080 USA

[2] Campbell Alliance, Thousand Oaks, CA 94080 USA

[3] Merck Sharp & Dohme R&D, Beijing 100015, Peoples R China

[4] Novartis Inst Biomed Res, Emeryville, CA 94608 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 11期

关键词：

Pim kinases; Kinase inhibitor; Structure based drug design; High throughput screening; Lead optimization; KINASE INHIBITORS; TARGET;

D O I：

10.1016/j.bmcl.2013.04.020

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms. (C) 2013 Elsevier Ltd. All rights reserved.

引用

收藏

页码：3149 / 3153

页数：5

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