Discovery of novel resorcinol diphenyl ether-based PROTAC-like molecules as dual inhibitors and degraders of PD-L1
Discovery of novel resorcinol diphenyl ether-based PROTAC-like molecules as dual inhibitors and degraders of PD-L1
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DOI：
10.1016/j.ejmech.2020.112377
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发表时间：
2020-08-01
影响因子：
6.7
通讯作者：
Chen, Jianjun
中科院分区：
文献类型：
--
作者：
Cheng, Binbin;Ren, Yichang;Chen, Jianjun
设计了新的基于间苯二酚二苯醚的PROTAC（PROteolysis Targeting Chimeras），并评估了它们对程序性细胞死亡-1/程序性细胞死亡-配体1（PD-1/PD-L1）途径的抑制活性及其降解PD-L1蛋白的能力。通过均相时间分辨荧光（HTRF）结合试验评估，大多数化合物显示出对PD-1/PD-L1的优异抑制活性，IC 50值范围为25 nM至200 nM。其中，化合物P22是最好的化合物之一，IC 50值为39.2 nM。除了抑制PD-1/PD-L1相互作用外，P22还显著恢复了Hep 3B/OS-8/hPD-L1和CD 3 T细胞共培养模型中抑制的免疫。流式细胞术（FCM）和Western blot结果表明，P22能够以溶酶体依赖的方式适度降低PD-L1的蛋白水平，这可能是P22发挥免疫作用的机制之一。初步的FCM和蛋白质印迹数据表明，基于PD-1/PD-L1小分子抑制剂构建PD-L1靶向PROTAC样分子是可能的，尽管这些化合物仅显示出适度的降解效率。总的来说，这项工作表明，P22可以作为探索PROTAC样策略降解PD-L1的起点。(C)2020 Elsevier Masson SAS。All rights reserved.
Novel resorcinol diphenyl ether-based PROTACs (PROteolysis TArgeting Chimeras) were designed and evaluated for their inhibitory activity against the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway and their ability to degrade PD-Ll protein. Most of the compounds displayed excellent inhibitory activities against PD-1/PD-L1, as assessed by the homogenous time-resolved fluorescence (HTRF) binding assay, with IC50 values ranging from 25 nM to 200 nM. Among them, compound P22 is one of the best with an IC50 value of 39.2 nM. In addition to inhibiting PD-1/PD-L1 interaction, P22 also significantly restored the immunity repressed in a co-culture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. Furthermore, flow cytometry (FCM) and western-blot data demonstrated that P22 could moderately reduce the protein levels of PD-L1 in a lysosome-dependent manner, which may contribute to its immune effects. Preliminary FCM and western-blot data suggest that it is possible to build PD-L1-targeting PROTAC-like molecules based on PD-1/PD-L1 small molecule inhibitors, though these compounds showed only modest degradation efficiencies. Collectively, this work suggests that P22 may serve as a starting point for exploring the degradation of PD-L1 by PROTAC-like strategy. (C) 2020 Elsevier Masson SAS. All rights reserved.