Comprehensive Cancer and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI, 48109, USA.
Life Sciences Institute, University of Michigan, 210 Washtenaw, Ann Arbor, MI, 48109, USA.
Angew Chem Int Ed Engl. 2018 Feb 5;57(6):1601-1605. doi: 10.1002/anie.201711828. Epub 2018 Jan 15.
The structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction is presented. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL-regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and co-crystal structure of M-525 in complex with menin firmly establish its mode of action. A single administration of M-525 effectively suppresses MLL-regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M-525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.
本文介绍了 M-525 的基于结构的设计，这是一种首创的、高活性、不可逆的小分子 menin-MLL 相互作用抑制剂。M-525 以亚纳摩尔浓度靶向细胞 menin 蛋白，在细胞生长抑制和 MLL 白血病细胞中抑制 MLL 调节的基因表达方面具有低纳摩尔效力。M-525 在非 MLL 白血病细胞中具有高细胞特异性，其效力比相应的可逆抑制剂高 30 多倍。M-525 与 menin 的质谱分析和共晶结构牢固确立了其作用模式。单次给予 M-525 可有效抑制肿瘤组织中 MLL 调节的基因表达。本文还开发了一种有效的 M-525 合成方法。这项研究表明，不可逆抑制 menin 可能是治疗 MLL 白血病的一种有前途的治疗策略。
