Binding-site switch of Protein Kinase CK2 inhibitors.

IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL ChemMedChem Pub Date : 2025-01-21 DOI:10.1002/cmdc.202400868
Isabelle Krimm, Dylan Grenier, Muriel Gelin, Yinshan Yang Cbs Cnrs Fr, Angélique Mularoni, Jean-François Guichou, Jean-Guy Delcros
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Abstract

The serine/threonine protein kinase CK2, a tetramer composed of a regulatory dimer (CK2β2) bound to two catalytic subunits CK2α, is a well-established therapeutic target for various pathologies, including cancer and viral infections. Several types of CK2 inhibitors have been developed, including inhibitors that bind to the catalytic ATP-site, bivalent inhibitors that occupy both the CK2α ATP-site and the αD pocket, and inhibitors that target the CK2α/CK2β interface. Interestingly, the bivalent inhibitor AB668 shares a similar chemical structure with the interface inhibitor CCH507. In this study, we designed analogs of CCH507 using structure-based and fragment-based approaches. The ability of these analogs to bind the CK2α/CK2β interface was evaluated using biolayer interferometry and fluorescence anisotropy-based assays. Their potency to inhibit CK2 kinase activity was determined using the bioluminescent ADP-Glo assay. These experiments allowed us to investigate which chemical modifications prevent the binding of the compounds at the CK2α/CK2β interface. Seven out of sixteen compounds conserved the ability to bind at the protein-protein interface, among which three compounds exhibited better interface inhibition compared to CCH507.

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蛋白激酶CK2抑制剂的结合位点转换。
丝氨酸/苏氨酸蛋白激酶CK2是一种由调节二聚体(CK2β2)与两个催化亚基CK2α结合组成的四聚体,是一种公认的治疗多种疾病的靶点,包括癌症和病毒感染。目前已经开发出几种类型的CK2抑制剂,包括结合催化atp位点的抑制剂,同时占据CK2α atp位点和αD口袋的二价抑制剂,以及靶向CK2α/CK2β界面的抑制剂。有趣的是,二价抑制剂AB668与界面抑制剂CCH507具有相似的化学结构。在本研究中,我们采用基于结构和基于片段的方法设计了CCH507的类似物。这些类似物结合CK2α/CK2β界面的能力通过生物层干涉法和基于荧光各向异性的测定来评估。采用生物发光ADP-Glo法测定其抑制CK2激酶活性的效力。这些实验使我们能够研究哪些化学修饰可以阻止化合物在CK2α/CK2β界面上的结合。16个化合物中有7个保留了蛋白-蛋白界面结合能力,其中3个化合物比CCH507表现出更好的界面抑制能力。
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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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