Discovery of 3, 5-substituted 6-azaindazoles as potent pan-Pim inhibitors. Issue 22 (15th November 2015)

• Record Type: Journal Article
• Authors: Hu, Huiyong; Wang, Xiaojing; Chan, Grace Ka Yan; Chang, Jae H.; Do, Steven; Drummond, Jake; Ebens, Allen; Lee, Wendy; Ly, Justin; Lyssikatos, Joseph P.; Murray, Jeremy; Moffat, John G.; Chao, Qi; Tsui, Vickie; Wallweber, Heidi; Kolesnikov, Aleksandr
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 22(2015)
• Page Start: 5258
• Page End: 5264
• Publication Date: 2015-11-15
• Subjects: Pim kinases -- Kinase inhibitor -- Screening -- Fragment based screen -- Structure based drug design -- Lead optimization; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.09.052
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 hit1 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 1 H -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.