9EO0
Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1
This is a non-PDB format compatible entry.
Summary for 9EO0
| Entry DOI | 10.2210/pdb9eo0/pdb |
| Descriptor | 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) |
| Functional Keywords | pd-l1, smi, nonsymmetrically, antitumor protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 6 |
| Total formula weight | 91799.97 |
| Authors | Plewka, J.,Hec, A.,Sitar, T.,Holak, T. (deposition date: 2024-03-14, release date: 2024-06-19, Last modification date: 2024-10-16) |
| Primary citation | 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 Cited by 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: 38894909DOI: 10.1021/acsmedchemlett.4c00042 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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