Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry
Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry
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DOI：
10.1021/acsmedchemlett.9b00541
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发表时间：
2020-05-14
影响因子：
4.2
通讯作者：
Hirsch, Anna K. H.
中科院分区：
文献类型：
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作者：
Hartman, Alwin M.;Elgaher, Walid A. M.;Hirsch, Anna K. H.
蛋白质-蛋白质相互作用（PPI）在许多生物学过程中发挥重要作用，如细胞周期调控和多种疾病。14-3-3蛋白家族是一个有吸引力的靶点，因为它们作为各种蛋白的结合伴侣，因此能够调节它们的生物活性。通过传统的筛选方法发现这种复合物的小分子调节剂，特别是稳定剂是一项具有挑战性的任务。在此，我们率先将动态组合化学（DCC）应用于PPI靶点，以寻找14-3-3蛋白质的调节剂。通过表面等离子体共振（SPR）对DCC实验扩增的命中物的结合亲和力进行评价，结果表明低微摩尔（K-D 15-16 μ M）酰基腙是14-3-3/突触足蛋白PPI稳定剂。因此，DCC似乎不仅非常适合于发现调节剂，而且还非常适合于发现众所周知的具有挑战性的PPI的更难以捉摸的稳定剂。
Protein-protein interactions (PPIs) play an important role in numerous biological processes such as cell-cycle regulation and multiple diseases. The family of 14-3-3 proteins is an attractive target as they serve as binding partner to various proteins and are therefore capable of regulating their biological activities. Discovering small-molecule modulators, in particular stabilizers, of such complexes via traditional screening approaches is a challenging task. Herein, we pioneered the first application of dynamic combinatorial chemistry (DCC) to a PPI target, to find modulators of 14-3-3 proteins. Evaluation of the amplified hits from the DCC experiments for their binding affinity via surface plasmon resonance (SPR), revealed that the low-micromolar (K-D 15-16 mu M) acylhydrazones are 14-3-3/synaptopodin PPI stabilizers. Thus, DCC appears to be ideally suited for the discovery of not only modulators but even the more elusive stabilizers of notoriously challenging PPIs.