Design and synthesis of benzylpiperidine inhibitors targeting the menin-MLL1 interface

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• 作者：Jing Ren^a ; ^c ; ^&dagger ; ; Wei Xu^b ; ^c ; ^&dagger ; ; Le Tang^a ; Minbo Su^b ; Danqi Chen^a ; Yue-Lei Chen^a ; ^c ; Yi Zang^b ; Jia Li^b ; ^c ; Jingkang Shen^a ; ^c ; Yubo Zhou^b ; ^c ; ^{ybzhou@simm.ac.cn" class="auth_mail" title="E-mail the corresponding author} ; Bing Xiong^a ; ^c ; ^{bxiong@simm.ac.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Menin ; Mixed lineage leukemia ; MLL1 ; SAR ; Inhibitor
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 September 2016
• 年：2016
• 卷：26
• 期：18
• 页码：4472-4476
• 全文大小：2160 K

文摘

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.