posted on 2024-02-13, 12:36authored byYongling Xu, Huijie Du, Weibo Guo, Beibei Liu, Wenxin Yan, Chi Zhang, Long Qin, Jingling Huang, Hongxia Wang, Shiqi Wu, Weijie Ren, Yi Zou, Jie Wang, Qihua Zhu, Yungen Xu, Hongfeng Gu
Inhibition
of the PD-1/PD-L1 interaction through small-molecule
inhibitors is a promising therapeutic approach in cancer immunotherapy.
Herein, we utilized BMS-202 as the lead compound to develop
a series of novel PD-1/PD-L1 small-molecule inhibitors with a naphthyridin
scaffold. Among these compounds, X14 displayed the most
potent inhibitory activity for the PD-1/PD-L1 interaction (IC50 = 15.73 nM). Furthermore, X14 exhibited good
binding affinity to both human PD-L1 (KD = 14.62 nM) and mouse PD-L1 (KD = 392
nM). In particular, X14 showed favorable pharmacokinetic
properties (oral bioavailability, F = 58.0%). In
the 4T1 (mouse breast cancer cells) syngeneic mouse model, intragastric
administration of X14 at 10 mg/kg displayed significant
antitumor efficacy (TGI = 66%). Mechanistic investigations revealed
that X14 effectively enhanced T-cell infiltration within
the tumor microenvironment. Our study demonstrates that compound X14 exhibits potential as a candidate compound for the development
of orally effective small-molecule inhibitors targeting PD-1/PD-L1.