Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
Laboratory of Chemical Biology, Department of Biomedical, Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Den Dolech 2, 5612, AZ, Eindhoven, The Netherlands.
Chemistry. 2020 Jun 2;26(31):7131-7139. doi: 10.1002/chem.202001608. Epub 2020 May 11.
Protein-protein interactions (PPIs) of 14-3-3 proteins are a model system for studying PPI stabilization. The complex natural product Fusicoccin A stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter. However, drug-like 14-3-3 PPI stabilizers enabling such studies have remained elusive. An X-ray crystal structure of a PPI in complex with an extremely low potency stabilizer uncovered an unexpected non-protein interacting, ligand-chelated Mg leading to the discovery of metal-ion-dependent 14-3-3 PPI stabilization potency. This originates from a novel chelation-controlled bioactive conformation stabilization effect. Metal chelation has been associated with pan-assay interference compounds (PAINS) and frequent hitter behavior, but chelation can evidently also lead to true potency gains and find use as a medicinal chemistry strategy to guide compound optimization. To demonstrate this, we exploited the effect to design the first potent, selective, and drug-like 14-3-3 PPI stabilizers.
蛋白质-蛋白质相互作用（PPIs）的 14-3-3 蛋白是研究 PPI 稳定化的模型系统。复杂的天然产物 Fusidic Acid A 稳定许多 14-3-3 PPIs，但不适用于 SAR 研究，这促使人们寻找更具类药性的化学物质。然而，能够进行此类研究的类药 14-3-3 PPI 稳定剂仍然难以捉摸。与一种极其低效力稳定剂结合的 PPI 的 X 射线晶体结构揭示了一种出乎意料的非蛋白相互作用的配体螯合 Mg，从而发现了依赖于金属离子的 14-3-3 PPI 稳定效力。这源于一种新型的螯合控制的生物活性构象稳定效应。金属螯合与全分析干扰化合物（PAINS）和频繁命中行为有关，但螯合显然也可以导致真正的效力提高，并作为一种药物化学策略来指导化合物优化。为了证明这一点，我们利用该效应设计了第一个有效、选择性和类药的 14-3-3 PPI 稳定剂。
