化学
Jurkat细胞
配体(生物化学)
程序性细胞死亡
流式细胞术
IC50型
立体化学
细胞凋亡
效力
T细胞
生物利用度
免疫系统
生物化学
药理学
受体
体外
分子生物学
生物
免疫学
作者
Tongfei Jing,Zhijing Zhang,Zhenghui Kang,Jianshan Mo,Xiaotong Yue,Ziyou Lin,Xiang Fu,Chang Liu,Hang Ma,Xiaolei Zhang,Wenhao Hu
标识
DOI:10.1021/acs.jmedchem.3c00205
摘要
A series of novel compounds bearing a cyclopropyl linkage were designed, synthesized, and evaluated as programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. An optimized compound (1S,2S)-A25 showed potent inhibitory activity against the PD-1/PD-L1 interaction (IC50 = 0.029 μM) with a selected binding affinity with PD-L1 (KD = 1.554 × 10–1 μM). Additionally, under the co-culture with H460/Jurkat cells, (1S,2S)-A25 can reduce the survival of H460 cells in a concentration-dependent way. A liver microsomal assay revealed that (1S,2S)-A25 had favorable metabolic stability. Furthermore, (1S,2S)-A25 displayed favorable pharmacokinetic properties (oral bioavailability of 21.58%) and potent antitumor potency in a LLC1 lung carcinoma model without observable side effects. Data from the flow cytometry and enzyme-linked immunosorbent assays demonstrated that (1S,2S)-A25 suppressed the tumor growth by activating the immune microenvironment. Our study suggests that (1S,2S)-A25 is a promising lead compound for the further development of PD-1/PD-L1 inhibitors.
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