9EO0

Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1

これはPDB形式変換不可エントリーです。

9EO0 の概要

• エントリーDOI: 10.2210/pdb9eo0/pdb
• 分子名称: Programmed cell death 1 ligand 1, ~{N}-[3-[3-[[5-[(2-hydroxyethylamino)methyl]pyridin-2-yl]carbonylamino]-2-methyl-phenyl]-2-methyl-phenyl]-5-[[3-(methylsulfonylamino)propylamino]methyl]pyridine-2-carboxamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: pd-l1, smi, nonsymmetrically, antitumor protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 91799.97

構造登録者

Plewka, J.,Hec, A.,Sitar, T.,Holak, T. (登録日: 2024-03-14, 公開日: 2024-06-19, 最終更新日: 2024-10-16)

主引用文献

Hec-Galazka, A.,Tyrcha, U.,Barczynski, J.,Bielski, P.,Mikitiuk, M.,Gudz, G.P.,Kitel, R.,Musielak, B.,Plewka, J.,Sitar, T.,Holak, T.A.
Nonsymmetrically Substituted 1,1'-Biphenyl-Based Small Molecule Inhibitors of the PD-1/PD-L1 Interaction.
Acs Med.Chem.Lett., 15:828-836, 2024

PubMed Abstract: Therapeutic antibodies directed against either programmed cell death-1 protein (PD-1) or its ligand PD-L1 have demonstrated efficacy in the treatment of various cancers. In contrast with antibodies, small molecules have the potential for increased tissue penetration; better pharmacology; and therefore, improved antitumor activity. A series of nonsymmetric C2 inhibitors were synthesized and evaluated for PD-1/PD-L1 interaction inhibition. These compounds induced PD-L1 dimerization and effectively blocked PD-L1/PD-1 interaction in a homogeneous time-resolved fluorescence (HTRF) assay with most inhibitors exhibiting IC values in the single-digit nM range and below. Their high inhibitory potency was also demonstrated in a cell-based coculture PD-1 signaling assay where exhibited an EC inhibitory activity of 21.8 nM, which approached that of the PD-L1 antibody durvalumab (EC = 0.3-1.8 nM). Structural insight into how these inhibitors interact with PD-L1 was gained by using NMR and X-ray cocrystal structure studies. These data support further preclinical evaluation of these compounds as antibody alternatives.

PubMed: 38894909
DOI: 10.1021/acsmedchemlett.4c00042

実験手法

X-RAY DIFFRACTION (2.5 Å)