Discovery and Optimization of 5-Hydroxy-Diclofenac toward a New Class of Ligands with Nanomolar Affinity for the CaMKIIα Hub Domain,Journal of Medicinal Chemistry

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Discovery and Optimization of 5-Hydroxy-Diclofenac toward a New Class of Ligands with Nanomolar Affinity for the CaMKIIα Hub Domain
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-05-02 , DOI: 10.1021/acs.jmedchem.1c02177
Yongsong Tian ₁ , Mohamed A Shehata ₁ , Stine Juul Gauger ₁ , Clarissa K L Ng ₁ , Sara Solbak ₁ , Louise Thiesen ₁ , Jesper Bruus-Jensen ₁ , Jacob Krall ₁ , Christoffer Bundgaard ₂ , K Michael Gibson ₃ , Petrine Wellendorph ₁ , Bente Frølund ₁

Affiliation

The Ca²⁺/calmodulin-dependent protein kinase II α (CaMKIIα) is a brain-relevant kinase involved in long-term potentiation and synaptic plasticity. We have recently pinpointed the CaMKIIα hub domain as the long-sought-after high-affinity target of γ-hydroxybutyrate ligands substantiated with a high-resolution cocrystal of 5-hydroxydiclofenac (3). Herein, we employed in silico approaches to rationalize and guide the synthesis and pharmacological characterization of a new series of analogues circumventing chemical stability problems associated with 3. The oxygen-bridged analogue 4d showed mid-nanomolar affinity and notable ligand-induced stabilization effects toward the CaMKIIα hub oligomer. Importantly, 4d displayed superior chemical and metabolic stability over 3 by showing excellent chemical stability in phosphate-buffered saline and high resistance to form reactive intermediates and subsequent sulfur conjugates. Altogether, our study highlights 4d as a new CaMKIIα hub high-affinity ligand with enhanced pharmacokinetic properties, representing a powerful tool compound for allosteric regulation of kinase activity with subtype specificity.

中文翻译：

5-羟基-双氯芬酸的发现和优化，用于对 CaMKIIα Hub 结构域具有纳摩尔亲和力的新型配体

Ca ²⁺ /钙调蛋白依赖性蛋白激酶 II α (CaMKIIα) 是一种脑相关激酶，参与长时程增强和突触可塑性。我们最近将 CaMKIIα 中枢结构域确定为备受追捧的 γ-羟基丁酸酯配体的高亲和力靶标，并得到了 5-羟基双氯芬酸的高分辨率共晶体的证实 ( 3 )。在这里，我们采用计算机方法来合理化和指导一系列新的类似物的合成和药理学表征，从而规避与3相关的化学稳定性问题。氧桥接类似物4d对 CaMKIIα 中枢寡聚体显示出中等纳摩尔亲和力和显着的配体诱导的稳定作用。重要的，通过在磷酸盐缓冲盐水中表现出优异的化学稳定性以及对形成反应性中间体和随后的硫缀合物的高抗性，4d表现出优于3的化学和代谢稳定性。总之，我们的研究强调了4d作为一种新的 CaMKIIα 中枢高亲和力配体，具有增强的药代动力学特性，代表了一种强大的工具化合物，用于对具有亚型特异性的激酶活性进行变构调节。

更新日期：2022-05-02

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