当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Interfering with the Tumor–Immune Interface: Making Way for Triazine-Based Small Molecules as Novel PD-L1 Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-20 , DOI: 10.1021/acs.jmedchem.1c01409 Pasquale Russomanno 1 , Giulia Assoni 2, 3 , Jussara Amato 1 , Vincenzo Maria D'Amore 1 , Riccardo Scaglia 3 , Diego Brancaccio 1 , Martina Pedrini 3 , Giovanna Polcaro 4 , Valeria La Pietra 1 , Paolo Orlando 3 , Marianna Falzoni 3 , Linda Cerofolini 5 , Stefano Giuntini 5 , Marco Fragai 5 , Bruno Pagano 1 , Greta Donati 1 , Ettore Novellino 6 , Cristina Quintavalle 7 , Gerolama Condorelli 7, 8 , Francesco Sabbatino 4 , Pierfausto Seneci 3 , Daniela Arosio 9 , Stefano Pepe 4 , Luciana Marinelli 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-20 , DOI: 10.1021/acs.jmedchem.1c01409 Pasquale Russomanno 1 , Giulia Assoni 2, 3 , Jussara Amato 1 , Vincenzo Maria D'Amore 1 , Riccardo Scaglia 3 , Diego Brancaccio 1 , Martina Pedrini 3 , Giovanna Polcaro 4 , Valeria La Pietra 1 , Paolo Orlando 3 , Marianna Falzoni 3 , Linda Cerofolini 5 , Stefano Giuntini 5 , Marco Fragai 5 , Bruno Pagano 1 , Greta Donati 1 , Ettore Novellino 6 , Cristina Quintavalle 7 , Gerolama Condorelli 7, 8 , Francesco Sabbatino 4 , Pierfausto Seneci 3 , Daniela Arosio 9 , Stefano Pepe 4 , Luciana Marinelli 1
Affiliation
|
The inhibition of the PD-1/PD-L1 axis by monoclonal antibodies has achieved remarkable success in treating a growing number of cancers. However, a novel class of small organic molecules, with BMS-202 (1) as the lead, is emerging as direct PD-L1 inhibitors. Herein, we report a series of 2,4,6-tri- and 2,4-disubstituted 1,3,5-triazines, which were synthesized and assayed for their PD-L1 binding by NMR and homogeneous time-resolved fluorescence. Among them, compound 10 demonstrated to strongly bind with the PD-L1 protein and challenged it in a co-culture of PD-L1 expressing cancer cells (PC9 and HCC827 cells) and peripheral blood mononuclear cells enhanced antitumor immune activity of the latter. Compound 10 significantly increased interferon γ release and apoptotic induction of cancer cells, with low cytotoxicity in healthy cells when compared to 1, thus paving the way for subsequent preclinical optimization and medical applications.
中文翻译：
干扰肿瘤免疫界面：让基于三嗪的小分子作为新型 PD-L1 抑制剂让路
单克隆抗体对 PD-1/PD-L1 轴的抑制在治疗越来越多的癌症方面取得了显著成功。然而，以 BMS-202 ( 1 ) 为先导的一类新型有机小分子作为直接 PD-L1 抑制剂正在兴起。在这里，我们报告了一系列 2,4,6-三和 2,4-二取代的 1,3,5-三嗪，它们被合成并通过 NMR 和均匀的时间分辨荧光测定其 PD-L1 结合。其中，化合物10与 PD-L1 蛋白强烈结合，并在表达 PD-L1 的癌细胞（PC9 和 HCC827 细胞）和外周血单核细胞的共培养中对其进行挑战，增强了后者的抗肿瘤免疫活性。化合物10显着增加干扰素γ释放和癌细胞的凋亡诱导，与1相比，在健康细胞中具有较低的细胞毒性，从而为后续的临床前优化和医学应用铺平了道路。
更新日期：2021-11-11
中文翻译：
干扰肿瘤免疫界面：让基于三嗪的小分子作为新型 PD-L1 抑制剂让路
单克隆抗体对 PD-1/PD-L1 轴的抑制在治疗越来越多的癌症方面取得了显著成功。然而，以 BMS-202 ( 1 ) 为先导的一类新型有机小分子作为直接 PD-L1 抑制剂正在兴起。在这里，我们报告了一系列 2,4,6-三和 2,4-二取代的 1,3,5-三嗪，它们被合成并通过 NMR 和均匀的时间分辨荧光测定其 PD-L1 结合。其中，化合物10与 PD-L1 蛋白强烈结合，并在表达 PD-L1 的癌细胞（PC9 和 HCC827 细胞）和外周血单核细胞的共培养中对其进行挑战，增强了后者的抗肿瘤免疫活性。化合物10显着增加干扰素γ释放和癌细胞的凋亡诱导，与1相比，在健康细胞中具有较低的细胞毒性，从而为后续的临床前优化和医学应用铺平了道路。
京公网安备 11010802027423号