Peptide-Directed Binding for the Discovery of Modulators of a-Helix-Mediated Protein-Protein Interactions: Proof-of-Concept Studies with the Apoptosis Regulator Mcl-1
Peptide-Directed Binding for the Discovery of Modulators of a-Helix-Mediated Protein-Protein Interactions: Proof-of-Concept Studies with the Apoptosis Regulator Mcl-1
复制标题
用于发现α-螺旋介导的蛋白质-蛋白质相互作用调节剂的肽定向结合：细胞凋亡调节剂 Mcl-1 的概念验证研究
DOI：
10.1002/ange.201705008
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发表时间：
2017
影响因子：
--
通讯作者：
Beekman A
中科院分区：
文献类型：
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作者：
Beekman A
由于大的疏水结合表面，以小分子为靶标的PPI可能是具有挑战性的。在这里，我们描述了一种利用选择性α-螺旋PPI的策略，将这些特征转移到小分子上。这一概念的证明是通过凋亡调节剂Mcl-1来证明的，这种调节剂通常被癌症用来避免细胞死亡。多肽定向结合使用很少的合成转化，需要生产少量的化合物，并产生高命中率。在这个例子中，大约50 %的制备的小分子的IC50值小于100 μm，大约25 %的小分子的IC50值低于1 μmto Mc1-1。化合物显示出对Mcl-1的选择性，对癌细胞具有细胞毒性，并诱导细胞凋亡。这种方法代表了快速发现新的α螺旋PPI调节器的一种新颖而经济的过程。
Targeting PPIs with small molecules can be challenging owing to large, hydrophobic binding surfaces. Herein, we describe a strategy that exploits selective α‐helical PPIs, transferring these characteristics to small molecules. The proof of concept is demonstrated with the apoptosis regulator Mcl‐1, commonly exploited by cancers to avoid cell death. Peptide‐directed binding uses few synthetic transformations, requires the production of a small number of compounds, and generates a high percentage of hits. In this example, about 50 % of the small molecules prepared showed an IC50value of less than 100 μm,and approximately 25 % had IC50values below 1 μmto Mcl‐1. Compounds show selectivity for Mcl‐1 over other anti‐apoptotic proteins, possess cytotoxicity to cancer cell lines, and induce hallmarks of apoptosis. This approach represents a novel and economic process for the rapid discovery of new α‐helical PPI modulators.