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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
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