Meden Anže, Claes Sandra, Van Loy Tom, Zorman Maša, Proj Matic, Schols Dominique, Gobec Stanislav, De Jonghe Steven
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular, Structural and Translational Virology Research Group, Herestraat 49, box 1043, 3000 Leuven, Belgium.
Bioorg Chem. 2025 Jun 1;159:108423. doi: 10.1016/j.bioorg.2025.108423. Epub 2025 Mar 29.
Despite the promise of the human chemokine receptor 7 (CCR7) as drug target for the treatment of cancer metastasis and autoimmune diseases, there are no potent and selective CCR7 antagonists known in literature. In this work, a 1,2,5-thiadiazole 1,1-dioxide with low μM activity as a CXCR2 and CCR7 antagonist was selected as starting point for a structure-activity relationship study. The replacement of the central thiadiazole dioxide motif with squaramide led to low nanomolar CCR7 antagonism. Additional systematic structural variations afforded various squaramide analogues that displayed potent CCR7 antagonism in a calcium mobilization assay with IC values in the low nM range. Unfortunately, the same compounds also displayed potent CXCR2 antagonistic activity and should therefore be considered as dual CCR7/CXCR2 antagonists.
尽管人趋化因子受体7（CCR7）有望成为治疗癌症转移和自身免疫性疾病的药物靶点，但文献中尚无已知的强效且选择性的CCR7拮抗剂。在这项工作中，选择了一种对CXCR2和CCR7具有低微摩尔活性的1,2,5-噻二唑1,1-二氧化物作为构效关系研究的起点。用方酸酰胺取代中心噻二唑二氧化物基序导致了低纳摩尔的CCR7拮抗作用。进一步的系统结构变化得到了各种方酸酰胺类似物，这些类似物在钙动员试验中表现出强效的CCR7拮抗作用，IC值在低纳摩尔范围内。不幸的是，同样的化合物也表现出强效的CXCR2拮抗活性，因此应被视为双CCR7/CXCR2拮抗剂。
