摘要
目的设计并合成新型联苯类PD-L1小分子抑制剂。方法以BMS-1018为先导化合物,通过变换苯环上取代基的相对位置,按照生物电子等排原理,结合分子对接技术,设计了3个系列联苯类目标化合物。采用均相时间分辨荧光法评价目标化合物对PD-1/PD-L1结合的抑制活性。结果与结论合成了10个未见文献报道的联苯类目标化合物,结构经^(1)H-NMR、ESI-MS谱确证。生物活性评价结果表明,大多数目标化合物对PD-L1显示不同程度的抑制活性。其中4个化合物A-1、A-3、A-4和C-2的活性较为突出,值得进一步研究。
Programmed cell death 1(PD-1)is an important immune checkpoint,which can induce apoptosis of antigen-specific T cells and reduce apoptosis in regulatory T cells.Programmed cell death ligand 1(PD-L1)is the critical ligand of PD-1,extensively expressed on the surface of marrow-derived cells,non-lymphoid tissues,solid organ and tumor cell.The block of PD-L1 expressed by host cell can promote tumor recession.Although anti-PD-1/PD-L1 antibodies have been approved for the treatment of multiple types of cancer,they may produce side effects because of their immunogenicity.Small molecule inhibitors of the PD-1/PD-L1 interaction can overcome the shortcomings.Bristol-Myers Squibb reported the small molecule inhibitors of PD-1/PD-L1,which can induce PD-L1 dimerization.Based on the reported PD-L1 inhibitor BMS-1018,ten biphenyl derivatives were designed and synthesized by swapping the position of the substitutes,bioisosterism and molecular docking technology.The structures of the target compounds were confirmed by^1H-NMR and ESI-MS.The inhibitory activities of these compounds against PD-L1 were determined by the homogenous time-resolved fluorescence(HTRF)binding assay.The results demonstrated that the target compounds showed varying degree of inhibitory effects on PD-L1.Among them,A-1,A-3,A-4 and C-2 displayed the most potent activity,suggesting that these compounds might be the candidates for further investigation.
作者
岳露
金双龙
高健
郭文洁
徐强
赖宜生
YUE Lu;JIN Shuang-long;GAO Jian;GUO Wen-jie;XU Qiang;LAI Yi-sheng(Center of Drug Discovery,State Key Laboratory of National Medicines,Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases,China Pharmaceutical University,Nanjing 210009,China;State Key Laboratory of Pharmaceutical Biotechnology,School of Life Sciences,Nanjing University,Nanjing 210093,China)
出处
《中国药物化学杂志》
CAS
CSCD
北大核心
2019年第6期417-425,共9页
Chinese Journal of Medicinal Chemistry
基金
国家自然科学基金项目(21772233).
