Rational Design of Selective Small-Molecule Inhibitors for β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interactions
Rational Design of Selective Small-Molecule Inhibitors for β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interactions
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DOI：
10.1021/jacs.5b04988
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发表时间：
2015-09-30
影响因子：
15
通讯作者：
Ji, Haitao
中科院分区：
文献类型：
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作者：
Hoggard, Logan R.;Zhang, Yongqiang;Ji, Haitao
利用有机小分子对α-螺旋介导的蛋白质 - 蛋白质相互作用（PPIs）进行选择性抑制，为化学探针和治疗药物的发现提供了巨大潜力。利用HippDB数据库对蛋白质数据库（Protein Data Bank）进行数据挖掘表明：（1）α-螺旋在位置i、i + 3和i + 7处的疏水突出热点的侧链在与第二个蛋白质相互作用时取向很少；（2）蛋白质 - 蛋白质相互作用复合物的热点口袋在与α-螺旋相同的疏水突出热点相互作用时具有不同的大小、形状和化学基团。基于这些观察结果，设计了一种有机小分子4'-氟 - N - 苯基 - [1,1'-联苯] - 3 - 甲酰胺作为通用支架，它本身直接模拟α-螺旋在位置i、i + 3和i + 7处疏水突出热点侧链的结合模式。对该通用支架进行便捷的修饰可导致对α-螺旋介导的蛋白质 - 蛋白质相互作用的选择性破坏。设计并合成了一系列对β - 连环蛋白/B细胞淋巴瘤9（BCL9）相对于β - 连环蛋白/钙黏蛋白蛋白质 - 蛋白质相互作用具有选择性的小分子抑制剂。通过定点突变和构效关系研究对新抑制剂的结合模式进行了表征。这类新型抑制剂能够选择性地破坏β - 连环蛋白/BCL9相对于β - 连环蛋白/钙黏蛋白的蛋白质 - 蛋白质相互作用，抑制经典Wnt信号通路的反式激活，下调Wnt靶基因的表达，并抑制Wnt/β - 连环蛋白依赖性癌细胞的生长。
Selective inhibition of alpha-helix-mediated protein-protein interactions (PPIs) with small organic molecules provides great potential for the discovery of chemical probes and therapeutic agents. Protein Data Bank data mining using the HippDB database indicated that (1) the side chains of hydrophobic projecting hot spots at positions i, i + 3, and i + 7 of an alpha-helix had few orientations when interacting with the second protein and (2) the hot spot pockets of PPI complexes had different sizes, shapes, and chemical groups when interacting with the same hydrophobic projecting hot spots of alpha-helix. On the basis of these observations, a small organic molecule, 4'-fluoro-N-phenyl-[1,1'-biphenyl]-3-carboxamide, was designed as a generic scaffold that itself directly mimics the binding mode of the side chains of hydrophobic projecting hot spots at positions i, i + 3, and i + 7 of an alpha-helix. Convenient decoration of this generic scaffold led to the selective disruption of alpha-helix-mediated PPIs. A series of small-molecule inhibitors selective for beta-catenin/B-cell lymphoma 9 (BCL9) over beta-catenin/cadherin PPIs was designed and synthesized. The binding mode of new inhibitors was characterized by site-directed mutagenesis and structure-activity relationship studies. This new class of inhibitors can selectively disrupt beta-catenin/BCL9 over beta-catenin/cadherin PPIs, suppress the transactivation of canonical Wnt signaling, downregulate the expression of Wnt target genes, and inhibit the growth of Wnt/beta-catenin-dependent cancer cells.