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

作者：Wang Xiaojing^*; Magnuson Steven; Pastor Rich; Fan Eric; Hu Huiyong; Tsui Vickie; Deng Wei; Murray Jeremy; Steffek Micah; Wallweber Heidi; Moffat John; Drummond Jason; Chan Grace; Harstad Eric; Ebens Allen J

来源：Bioorganic & Medicinal Chemistry Letters, 2013, 23(11): 3149-3153.

DOI：10.1016/j.bmcl.2013.04.020

• Pim kinases
• Kinase inhibitor
• Structure based drug design
• High throughput screening
• Lead optimization

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.

• 出版日期2013-6-1