1. Discovery of quinazoline derivatives as novel small-molecule inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction
Yu Wang, Kun Huang, Yali Gao, Dandan Yuan, Lin Ling, Jieqing Liu, Sihai Wu, Roufen Chen, He Li, Yizu Xiong, Han Liu, Junjie Ma Eur J Med Chem. 2022 Feb 5;229:113998. doi: 10.1016/j.ejmech.2021.113998. Epub 2021 Nov 18.
Development of small molecule PD-1/PD-L1 inhibitors as a novel immunotherapy strategy exhibits great promise. Herein, a novel series of quinazoline derivatives were designed, synthesized and their inhibitory activity against the PD-1/PD-L1 interaction was evaluated through a homogenous time-resolved fluorescence (HTRF) assay. Among them, the compound 39 exhibited the most potent inhibitory activity with an IC50 value of 1.57 nM. Furthermore, the cellular level assays revealed that 39 could inhibit the PD-1/PD-L1 interaction and restore T-cell function, and showed low toxicity on the PBMCs. In addition, the structure-activity relationships (SARs) of the novel quinazoline derivatives were explored and the binding mode of 39 with dimeric PD-L1 was analyzed by molecular docking. This work demonstrates that incorporation of pyrimidine group between the 2 and 3-positions of the biphenyl structure is an effective strategy for designing novel and more potent small molecule PD-1/PD-L1 inhibitors, and 39 can be regarded as a promising lead compound for further investigation.
2. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1)
Krzysztof M Zak, Przemyslaw Grudnik, Katarzyna Guzik, Bartosz J Zieba, Bogdan Musielak, Alexander Dömling, Grzegorz Dubin, Tad A Holak Oncotarget. 2016 May 24;7(21):30323-35. doi: 10.18632/oncotarget.8730.
Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has provided unprecedented results in cancer treatment in the recent years. Development of chemical inhibitors for this pathway lags the antibody development because of insufficient structural information. The first nonpeptidic chemical inhibitors that target the PD-1/PD-L1 interaction have only been recently disclosed by Bristol-Myers Squibb. Here, we show that these small-molecule compounds bind directly to PD-L1 and that they potently block PD-1 binding. Structural studies reveal a dimeric protein complex with a single small molecule which stabilizes the dimer thus occluding the PD-1 interaction surface of PD-L1s. The small-molecule interaction "hot spots" on PD-L1 surfaces suggest approaches for the PD-1/PD-L1 antagonist drug discovery.
3. Novel Biphenyl Pyridines as Potent Small-Molecule Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction
Tianyu Wang, Shi Cai, Mingming Wang, Wanheng Zhang, Kuojun Zhang, Dong Chen, Zheng Li, Sheng Jiang J Med Chem. 2021 Jun 10;64(11):7390-7403. doi: 10.1021/acs.jmedchem.1c00010. Epub 2021 May 30.
With the successful clinical application of anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies (mAb), targeting the PD-1/PD-L1 interaction has become a promising method for the discovery of cancer therapy. Due to the inherent limitations of antibodies, it is necessary to search for small-molecule inhibitors against the PD-1/PD-L1 axis. We report the design, synthesis, and evaluation in vitro and in vivo of a series of novel biphenyl pyridines as the inhibitors of PD-1/PD-L1. 2-(((2-Methoxy-6-(2-methyl-[1,1'-biphenyl]-3-yl)pyridin-3-yl)methyl)amino)ethan-1-ol (24) was found to inhibit the PD-1/PD-L1 interaction with an IC50 value of 3.8 ± 0.3 nM and enhance the killing activity of tumor cells by immune cells. Compound 24 displays great pharmacokinetics (oral bioavailability of 22%) and significant in vivo antitumor activity in a CT26 mouse model. Flow cytometry and immunohistochemistry data indicated that compound 24 activates the immune activity in tumors. These results suggest that compound 24 is a promising small-molecule inhibitor against the PD-1/PD-L1 axis and merits further development.