Van Hoof Max, Claes Sandra, Proj Matic, Van Loy Tom, Schols Dominique, Gobec Stanislav, Dehaen Wim, De Jonghe Steven
Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001, Leuven, Belgium.
KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, box 1043, 3000, Leuven, Belgium.
Eur J Med Chem. 2023 May 5;251:115240. doi: 10.1016/j.ejmech.2023.115240. Epub 2023 Mar 5.
CCR7 signaling directs the migration of both immune cells and cancer cells to the lymph nodes, is involved in numerous chronic inflammatory disorders and lymph node metastases. Despite the therapeutic promise of CCR7 antagonists, no potent and selective small molecule CCR7 antagonists have been reported to date. Since most human chemokine G protein-coupled receptors (GPCRs) share a conserved intracellular allosteric binding site, new CCR7 antagonist chemotypes may be identified by screening small molecules that are known to target this site in other chemokine GPCRs. In this work, our previously prepared series of 14 scaffold-modified analogues of a known thiazolo[4,5-d]pyrimidine CXCR2 antagonist were screened as potential CCR7 antagonists. This resulted in the discovery of a triazolo[4,5-d]pyrimidine analogue with an IC of 2.43 μM against CCR7 and 0.66 μM against CXCR2. Exploration of the structure-activity relationship (SAR) for the 3-, 5- and 7-position substituents of this triazolo[4,5-d]pyrimidine resulted in improved potency and selectivity, with an IC of 0.43 μM and 11.02 μM against CCR7 and CXCR2, respectively, for the most selective derivative. Molecular docking showed that the binding mode of these triazolo[4,5-d]pyrimidines in CCR7 and CXCR2 corresponds with those of previously co-crystallized ligands.
CCR7信号传导引导免疫细胞和癌细胞迁移至淋巴结，参与多种慢性炎症性疾病及淋巴结转移。尽管CCR7拮抗剂具有治疗前景，但迄今为止尚未报道有强效且选择性的小分子CCR7拮抗剂。由于大多数人类趋化因子G蛋白偶联受体（GPCR）共享一个保守的细胞内变构结合位点，因此可通过筛选已知靶向其他趋化因子GPCR中该位点的小分子来鉴定新的CCR7拮抗剂化学类型。在这项工作中，我们将先前制备的一系列已知噻唑并[4,5-d]嘧啶CXCR2拮抗剂的14种骨架修饰类似物作为潜在的CCR7拮抗剂进行筛选。这导致发现了一种三唑并[4,5-d]嘧啶类似物，其对CCR7的IC50为2.43 μM，对CXCR2的IC50为0.66 μM。对该三唑并[4,5-d]嘧啶的3、5和7位取代基的构效关系（SAR）进行探索，提高了活性和选择性，对于最具选择性的衍生物，其对CCR7和CXCR2的IC50分别为0.43 μM和11.02 μM。分子对接表明，这些三唑并[4,5-d]嘧啶在CCR7和CXCR2中的结合模式与先前共结晶配体的结合模式一致。
