Unveiling new chemical scaffolds as Mnk inhibitors. (March 2016)

• Record Type: Journal Article
• Authors: Diab, Sarah; Li, Peng; Basnet, Sunita KC; Lu, Jingfeng; Yu, Mingfeng; Albrecht, Hugo; Milne, Robert W; Wang, Shudong
• Is Part Of: Future medicinal chemistry. Volume 8:Number 3(2016)
• Page Start: 271
• Page End: 285
• Publication Date: 2016-03
• Subjects: AML -- anti-cancer drug discovery -- CGP57380 -- eIF4E phosphorylation -- Mnk kinase inhibitors; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc.15.190
• Languages: English
• ISSNs: 1756-8919

Abstract

The discovery of small molecules that selectively inhibit Mnks is considered of paramount importance towards deciphering the exact role of these proteins in carcinogenesis and to further validate them as anti-cancer drug targets. However, the dearth of structural information of Mnks is a major hurdle. This study unveils the 7 H -pyrrolo[2, 3- d ]pyrimidine derivatives as potent inhibitors of Mnks. ATP and substrate competition assays showed that this scaffold interacts with the ATP binding site, but not with the substrate site. Screened against a panel of cancer cells, Mnk inhibitors were most potent against MV4-11 acute myeloid leukemia cells. The induction of apoptosis was shown to be mediated by downregulation of Mcl-1.