Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370, Wrocław, Poland.
Department of Pathology, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, United States.
Eur J Med Chem. 2020 Dec 1;207:112748. doi: 10.1016/j.ejmech.2020.112748. Epub 2020 Aug 20.
The interaction between menin and mixed lineage leukemia (MLL) was identified as an interesting target for treating some cancers including acute leukemia. On the basis of the known crystal structure of the MBM1-menin complex (MBM - menin binding motif), several cyclic peptides were designed. Elaboration of the effective cyclization strategy using a metathesis reaction allowed for a successfully large number of derivatives to be obtained. Subsequent optimization of the loop size, as well as N-terminal, central and C-terminal parts of the studied peptides resulted in structures exhibiting low nanomolar activities. A crystal structure of an inhibitor-menin complex revealed a compact conformation of the ligand molecule, which is stabilized not only by the introduction of a covalent linker but also three intramolecular hydrogen bonds. The inhibitor adopts a figure eight-like conformation, which perfectly fits the cleft of menin. We demonstrated that the development of compact, miniprotein-like structures is a highly effective approach for inhibition of protein-protein interactions.
Menin 与混合谱系白血病（MLL）的相互作用被确定为治疗某些癌症（包括急性白血病）的一个有趣的靶点。基于已知的 MBM1-menin 复合物（MBM-menin 结合基序）的晶体结构，设计了几种环肽。使用复分解反应精心设计有效的环化策略，成功获得了大量的衍生物。随后对研究肽的环大小以及 N 端、中央和 C 端进行优化，得到了具有低纳摩尔活性的结构。抑制剂与 menin 复合物的晶体结构揭示了配体分子的紧凑构象，这种构象不仅通过引入共价连接子而且通过三个分子内氢键得到稳定。抑制剂采用类似 8 字形的构象，完美契合 menin 的裂缝。我们证明了开发紧凑的、类似小蛋白的结构是抑制蛋白质-蛋白质相互作用的一种非常有效的方法。
