Department of Organic Chemistry, Faculty of Chemistry , Jagiellonian University , Gronostajowa 2 , 30-387 Krakow , Poland.
The Cancer Institute of New Jersey , New Brunswick , New Jersey 08901 , United States.
J Med Chem. 2019 Aug 8;62(15):7250-7263. doi: 10.1021/acs.jmedchem.9b00795. Epub 2019 Jul 25.
A series of -symmetric inhibitors was designed and evaluated for inhibitory activity against the programmed cell death-1/programmed death-ligand 1(PD-1/PD-L1) protein-protein interaction (PPI) in a homogenous time-resolved fluorescence (HTRF) assay and PD-1 signaling in cell-based coculture assays. -symmetric inhibitors (LH1306) and (LH1307) exhibited IC values of 25 and 3.0 nM, respectively, in the HTRF assay. While was ∼3.8-fold more potent than previously reported inhibitor , could not be differentiated from due to their high potency and the limit of our HTRF assay conditions. In one cell-based coculture PD-1 signaling assay, and were 8.2- and 2.8-fold more potent in inhibiting PD-1 signaling than and , respectively. NMR and X-ray cocrystal structural studies provided more structural insights into the interaction between and PD-L1; binds to PD-L1 at the PD-1 binding site and induces the formation of a more symmetrically arranged PD-L1 homodimer than that previously reported for other inhibitors.
设计并评价了一系列 -对称抑制剂对 PD-1/PD-L1（程序性死亡受体 1/程序性死亡配体 1）蛋白-蛋白相互作用（PPI）的抑制活性，以及在基于细胞共培养测定中 PD-1 信号的抑制活性。-对称抑制剂（LH1306）和（LH1307）在 HTRF 测定中分别显示出 25 和 3.0 nM 的 IC 值。虽然 比之前报道的抑制剂 约强 3.8 倍，但由于其高效力和我们 HTRF 测定条件的限制，无法将其与 区分开来。在一种基于细胞的共培养 PD-1 信号测定中， 和 抑制 PD-1 信号的效力分别比 和 强 8.2 倍和 2.8 倍。NMR 和 X 射线共晶结构研究为 和 PD-L1 之间的相互作用提供了更多的结构见解； 与 PD-L1 在 PD-1 结合位点结合，并诱导形成比以前报道的其他抑制剂更对称排列的 PD-L1 同源二聚体。
