Discovery of 3,5-substituted 6-azaindazoles as potent pan-Pim inhibitors

详细信息    查看全文

• 作者：Huiyong Hu^a ; Xiaojing Wang^a ; Grace Ka Yan Chan^a ; Jae H. Chang^a ; Steven Do^a ; Jake Drummond^a ; Allen Ebens^b ; Wendy Lee^a ; Justin Ly^a ; Joseph P. Lyssikatos^c ; Jeremy Murray^a ; John G. Moffat^a ; Qi Chao^d ; Vickie Tsui^a ; Heidi Wallweber^a ; Aleksandr Kolesnikov^a ;
• 关键词：Pim kinases ; Kinase inhibitor ; Screening ; Fragment based screen ; Structure based drug design ; Lead optimization
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：15 November 2015
• 年：2015
• 卷：25
• 期：22
• 页码：5258-5264
• 全文大小：4097 K

文摘

Pim kinase inhibitors are promising cancer therapeutics. Pim-2, among the three Pim isoforms, plays a critical role in multiple myeloma yet inhibition of Pim-2 is challenging due to its high affinity for ATP. A co-crystal structure of a screening hit 1 bound to Pim-1 kinase revealed the key binding interactions of its indazole core within the ATP binding site. Screening of analogous core fragments afforded 1H-pyrazolo[3,4-c]pyridine (6-azaindazole) as a core for the development of pan-Pim inhibitors. Fragment and structure based drug design led to identification of the series with picomolar biochemical potency against all three Pim isoforms. Desirable cellular potency was also achieved.