Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFβ
Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFβ
复制标题
DOI：
10.1016/j.chembiol.2007.09.006
复制
发表时间：
2007-10-01
影响因子：
--
通讯作者：
Bushweller, John H.
中科院分区：
文献类型：
--
作者：
Gorczynski, Michael J.;Grembecka, Jolanta;Bushweller, John H.
核心结合因子的两个亚基（Runx 1和CBF β）在造血中起关键作用，并且是白血病中发现的染色体易位的常见靶点。CBF β-平滑肌肌球蛋白重链（SMMHC）融合蛋白与Runx 1的结合对于白血病的发生是必不可少的，使其成为治疗的可行靶点。我们已经开发了具有低微摩尔亲和力的抑制剂，其有效地阻断Runx 1与CBF β的结合。基于NMR的对接显示，这些化合物在从Runx 1的结合界面移位的位点处与CBF β结合，也就是说，这些化合物充当这种蛋白质-蛋白质相互作用的变构抑制剂，这是一种潜在的可推广的方法。用这些化合物处理人白血病细胞系ME-1显示增殖降低，表明这些是进一步开发的良好候选物。
The two subunits of core binding factor (Runx1 and CBF beta) play critical roles in hematopoiesis and are frequent targets of chromosomal translocations found in leukemia. The binding of the CBF beta-smooth muscle myosin heavy chain (SMMHC) fusion protein to Runx1 is essential for leukemogenesis, making this a viable target for treatment. We have developed inhibitors with low micromolar affinity which effectively block binding of Runx1 to CBF beta. NMR-based docking shows that these compounds bind to CBF beta at a site displaced from the binding interface for Runx1, that is, these compounds function as allosteric inhibitors of this protein-protein interaction, a potentially generalizable approach. Treatment of the human leukemia cell line ME-1 with these compounds shows decreased proliferation, indicating these are good candidates for further development.