Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry.,ACS Medicinal Chemistry Letters

当前位置： X-MOL 学术 › ACS Med. Chem. Lett. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-02-28 , DOI: 10.1021/acsmedchemlett.9b00541
Alwin M Hartman _{1,

2,

3} , Walid A M Elgaher ₂ , Nathalie Hertrich ₂ , Sebastian A Andrei ₄ , Christian Ottmann _{4,

5} , Anna K H Hirsch _{1,

2,

3}

Affiliation

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 μM) 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.

中文翻译：

通过动态组合化学发现14-3-3蛋白-蛋白质相互作用的小分子稳定剂。

蛋白质-蛋白质相互作用（PPI）在许多生物过程（例如细胞周期调节和多种疾病）中起着重要作用。14-3-3蛋白家族是有吸引力的靶标，因为它们充当各种蛋白的结合伴侣，因此能够调节其生物学活性。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艰巨的任务。在此，我们率先将动态组合化学（DCC）应用于PPI目标，以发现14-3-3蛋白的调节剂。通过表面等离振子共振（SPR）对DCC实验中扩增出的命中分子的结合亲和力进行评估后发现，低微摩尔（KD 15-16μM）的酰基nes是14-3-3 /突触足蛋白PPI稳定剂。从而，

更新日期：2020-02-28

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11