Wurnig Silas L, Huber Max E, Weiler Corinna, Baltrukevich Hanna, Merten Nicole, Stötzel Isabel, Steffen Teresa, Chang Yinshui, Klammer René H L, Baumjohann Dirk, Kiermaier Eva, Kolb Peter, Kostenis Evi, Schiedel Matthias, Hansen Finn K
Department of Pharmaceutical & Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, Bonn 53121, Germany.
Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, Erlangen 91058, Germany.
J Med Chem. 2025 Feb 27;68(4):4308-4333. doi: 10.1021/acs.jmedchem.4c02102. Epub 2025 Feb 12.
Intracellular ligands of G protein-coupled receptors (GPCRs) are gaining significant interest in drug discovery. Here, we report the development of the fluorescent ligand Mz437 () targeting the CC chemokine receptor CCR7 at an intracellular allosteric site. We demonstrate its experimental power by applying to identify two improved intracellular CCR7 antagonists, SLW131 () and SLW132 (), developed by converting two weakly active antagonists into single- or double-digit nanomolar ligands with minimal modifications. The thiadiazoledioxide was derived from the CCR7 antagonist Cmp2105 by removing a methyl group from the benzamide moiety, while the squaramide was obtained from the CXCR1/CXCR2 antagonist and clinical candidate navarixin by replacing the ethyl substituent by a -butyl group to engage a lipophilic subpocket. We show that and qualify to probe CCR7 biology in recombinant and primary immune cells and expect our novel probes to facilitate the design of next-generation intracellular CCR7 ligands.
G蛋白偶联受体（GPCRs）的细胞内配体在药物研发中越来越受到关注。在此，我们报告了荧光配体Mz437（）的开发，该配体靶向CC趋化因子受体CCR7的细胞内变构位点。我们通过应用它来鉴定两种改进的细胞内CCR7拮抗剂SLW131（）和SLW132（），展示了其实验能力，这两种拮抗剂是通过对两种活性较弱的拮抗剂进行最小程度的修饰，将其转化为纳摩尔级的单或双位数配体而开发的。噻二唑二氧化物是通过从苯甲酰胺部分去除一个甲基，从CCR7拮抗剂Cmp2105衍生而来，而方酸二酰胺是通过将乙基取代基替换为丁基以结合一个亲脂性亚口袋，从CXCR1/CXCR2拮抗剂及临床候选药物那伐瑞新获得的。我们表明，SLW131和SLW132有资格在重组和原代免疫细胞中探测CCR7生物学特性，并期望我们的新型探针能够促进下一代细胞内CCR7配体的设计。
