8OR1

Co-crystal strucutre of PD-L1 with low molecular weight inhibitor

8OR1 の概要

• エントリーDOI: 10.2210/pdb8or1/pdb
• 分子名称: Programmed cell death 1 ligand 1, 5-[[5-[[2-chloranyl-3-(2-fluorophenyl)phenyl]methoxy]-2-[(~{E})-2-hydroxyethyliminomethyl]phenoxy]methyl]pyridine-3-carbonitrile (2 entities in total)
• 機能のキーワード: pd-l1, inhibitor, immunotheraphy, immune system
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 26980.38

構造登録者

Zhang, H.,Zhou, S.,Wu, C.,Zhu, M.,Yu, Q.,Wang, X.,Awadasseid, A.,Plewka, J.,Magiera-Mularz, K.,Wu, Y.,Zhang, W. (登録日: 2023-04-12, 公開日: 2023-08-02, 最終更新日: 2023-08-23)

主引用文献

Zhang, H.,Zhou, S.,Plewka, J.,Wu, C.,Zhu, M.,Yu, Q.,Musielak, B.,Wang, X.,Awadasseid, A.,Magiera-Mularz, K.,Wu, Y.,Zhang, W.
Design, Synthesis, and Antitumor Activity Evaluation of 2-Arylmethoxy-4-(2,2'-dihalogen-substituted biphenyl-3-ylmethoxy) Benzylamine Derivatives as Potent PD-1/PD-L1 Inhibitors.
J.Med.Chem., 66:10579-10603, 2023

PubMed Abstract: Novel 2-arylmethoxy-4-(2,2'-dihalogen-substituted biphenyl-3-ylmethoxy) benzylamine derivatives were designed, synthesized, and evaluated and against cancers as PD-1/PD-L1 inhibitors. Through the computer-aided structural optimization and the homogeneous time-resolved fluorescence (HTRF) assay, compound was found to most strongly block the PD-1/PD-L1 interaction with an IC value of 2.4 ± 0.8 nM and showed the most potent activity. H NMR titration results indicated that can tightly bind to the PD-L1 protein with < 1 μM. The X-ray diffraction data for the cocrystal structure of the PD-L1 complex (3.5 Å) deciphered a novel binding mode in detail, which can account for its most potent inhibitory activity. Cell-based assays further demonstrated the strong ability of as an hPD-1/hPD-L1 blocker. Especially in an hPD-L1 MC38 humanized mouse model, significantly inhibited tumor growth without obvious toxicity, with a TGI rate of 55.20% (50 mg/kg, i.g.). In conclusion, is a promising clinical candidate worthy of further development.

PubMed: 37496104
DOI: 10.1021/acs.jmedchem.3c00731

実験手法

X-RAY DIFFRACTION (3.5 Å)