Design and synthesis of benzylpiperidine inhibitors targeting the menin-MLL1 interface
- Bioorg Med Chem Lett. 2016 Sep 15;26(18):4472-4476. doi: 10.1016/j.bmcl.2016.07.074.
- 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China.
- 2. The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China.
- 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
- 4. The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China.
- 5. The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China. Electronic address: [email protected].
- 6. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China. Electronic address: [email protected].
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.