8P1O

Solubilizer tag effect on PD-L1/inhibitor binding properties for m-terphenyl derivatives

「8R6Q」から置き換えられました

8P1O の概要

• エントリーDOI: 10.2210/pdb8p1o/pdb
• 分子名称: Programmed cell death 1 ligand 1, (3~{R})-1-[[4-[2-chloranyl-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-methoxy-phenyl]methyl]-~{N}-(2-hydroxyethyl)pyrrolidine-3-carboxamide, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: pd-l1, immune checkpoint, small-molecule inhibitor, cancer, m-terphenyl, 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: 34254.56

構造登録者

Plewka, J.,Magiera-Mularz, K.,Surmiak, E.,Kalinowska-Tluscik, J.,Holak, T.A. (登録日: 2023-05-12, 公開日: 2024-01-31, 最終更新日: 2025-12-03)

主引用文献

Surmiak, E.,Zaber, J.,Plewka, J.,Wojtanowicz, G.,Kocik-Krol, J.,Kruc, O.,Muszak, D.,Rodriguez, I.,Musielak, B.,Viviano, M.,Castellano, S.,Skalniak, L.,Magiera-Mularz, K.,Holak, T.A.,Kalinowska-Tluscik, J.
Solubilizer Tag Effect on PD-L1/Inhibitor Binding Properties for m -Terphenyl Derivatives.
Acs Med.Chem.Lett., 15:36-44, 2024

PubMed Abstract: Although heavily studied, the subject of anti-PD-L1 small-molecule inhibitors is still elusive. Here we present a systematic overview of the principles behind successful anti-PD-L1 small-molecule inhibitor design on the example of the -terphenyl scaffold, with a particular focus on the neglected influence of the solubilizer tag on the overall affinity toward PD-L1. The inhibitor developed according to the proposed guidelines was characterized through its potency in blocking PD-1/PD-L1 complex formation in homogeneous time-resolved fluorescence and cell-based assays. The affinity is also explained based on the crystal structure of the inhibitor itself and its costructure with PD-L1 as well as a molecular modeling study. Our results structuralize the knowledge related to the strong pharmacophore feature of the -terphenyl scaffold preferential geometry and the more complex role of the solubilizer tag in PD-L1 homodimer stabilization.

PubMed: 38229762
DOI: 10.1021/acsmedchemlett.3c00306

実験手法

X-RAY DIFFRACTION (2.17 Å)