Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Blood. 2012 Nov 29;120(23):4461-9. doi: 10.1182/blood-2012-05-429274. Epub 2012 Aug 30.
Menin functions as a critical oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving 2 N-terminal fragments of MLL. In the present study, we reveal the first high-resolution crystal structure of human menin in complex with a small-molecule inhibitor of the menin-MLL interaction, MI-2. The structure shows that the compound binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin-MI-2 structure, we developed MI-2-2, a compound that binds to menin with low nanomolar affinity (K(d) = 22nM) and very effectively disrupts the bivalent protein-protein interaction between menin and MLL. MI-2-2 demonstrated specific and very pronounced activity in MLL leukemia cells, including inhibition of cell proliferation, down-regulation of Hoxa9 expression, and differentiation. Our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting of the menin-MLL interaction in leukemia and demonstrate a proof of concept that inhibition of complex multivalent protein-protein interactions can be achieved by a small-molecule inhibitor.
Menin 作为混合谱系白血病 (MLL) 融合蛋白的关键致癌辅助因子，在急性白血病的发展中起作用，抑制 menin 与 MLL 融合蛋白的相互作用代表了一种非常有前途的策略，可以逆转其致癌活性。MLL 以涉及 MLL 的 2 个 N 端片段的二价模式与 menin 相互作用。在本研究中，我们揭示了人 menin 与 menin-MLL 相互作用的小分子抑制剂 MI-2 的第一个高分辨率晶体结构。该结构表明，该化合物结合到 menin 中的 MLL 口袋中，并模拟了 MLL 与 menin 的关键相互作用。基于 menin-MI-2 结构，我们开发了 MI-2-2，该化合物与 menin 的结合具有低纳摩尔亲和力（K(d) = 22nM），并非常有效地破坏 menin 和 MLL 之间的二价蛋白-蛋白相互作用。MI-2-2 在 MLL 白血病细胞中表现出特异性和非常明显的活性，包括抑制细胞增殖、下调 Hoxa9 表达和分化。我们的结果为设计下一代抑制剂提供了合理且必不可少的结构基础，以有效靶向白血病中的 menin-MLL 相互作用，并证明了通过小分子抑制剂抑制复杂的多价蛋白-蛋白相互作用是可行的。
