Design and synthesis of benzylpiperidine inhibitors targeting the menin–MLL1 interface. Issue 18 (15th September 2016)

• Record Type: Journal Article
• Authors: Ren, Jing; Xu, Wei; Tang, Le; Su, Minbo; Chen, Danqi; Chen, Yue-Lei; Zang, Yi; Li, Jia; Shen, Jingkang; Zhou, Yubo; Xiong, Bing
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 18(2016)
• Page Start: 4472
• Page End: 4476
• Publication Date: 2016-09-15
• Subjects: Menin -- Mixed lineage leukemia -- MLL1 -- SAR -- Inhibitor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.07.074
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Menin is an essential oncogenic cofactor for mixed lineage leukemia (MLL)-mediated leukemogenesis, functioning through its direct interaction with MLL1 protein. Therefore, targeting the menin–MLL1 protein–protein interface represents a promising strategy to block MLL-mediated leukemogenesis. On the basis of co-crystal structure analysis, starting from thienopyrimidine chemotype, we have investigated the detailed structure–activity relationship of the piperazinyl-dihydrothiazole moiety. Several compounds were found with potent inhibitory activity against menin and better activities in cell-based experiments than MI-2-2. Molecular docking analysis revealed a less explored subpocket, which could be used for the design of new menin–MLL1 inhibitors.