9ERY

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

Summary for 9ERY

• Entry DOI: 10.2210/pdb9ery/pdb
• Descriptor: Programmed cell death 1 ligand 1, 5-[[5-[[2-[bis(fluoranyl)methyl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]methoxy]-2-[(2-hydroxyethylamino)methyl]phenoxy]methyl]pyridine-3-carbonitrile, SULFATE ION, ... (4 entities in total)
• Functional Keywords: pd-l1, inhibitor, immunotheraphy, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 30577.82

Authors

Plewka, J.,Magiera-Mularz, K.,Zhang, W. (deposition date: 2024-03-25, release date: 2024-07-24, Last modification date: 2024-10-23)

Primary citation

Zhang, F.,Zhang, H.,Zhou, S.,Plewka, J.,Wang, M.,Sun, S.,Wu, C.,Yu, Q.,Zhu, M.,Awadasseid, A.,Wu, Y.,Magiera-Mularz, K.,Zhang, W.
Design, synthesis, and evaluation of antitumor activity of 2-arylmethoxy-4-(2-fluoromethyl-biphenyl-3-ylmethoxy) benzylamine derivatives as PD-1/PD-l1 inhibitors.
Eur.J.Med.Chem., 276:116683-116683, 2024

PubMed Abstract: A series of novel 2-arylmethoxy-4-(2-fluoromethyl-biphenyl-3-ylmethoxy) benzylamine derivatives was designed, synthesized, and evaluated for their antitumor effects as PD-1/PD-L1 inhibitors both in vitro and in vivo. Firstly, the ability of these compounds to block the PD-1/PD-L1 immune checkpoint was assessed using the homogeneous time-resolved fluorescence (HTRF) assay. Two of the compounds can strongly block the PD-1/PD-L1 interaction, with IC values of less than 10 nM, notably, compound HD10 exhibited significant clinical potential by inhibiting the PD-1/PD-L1 interaction with an IC value of 3.1 nM. Further microscale thermophoresis (MST) analysis demonstrated that HD10 had strong interaction with PD-L1 protein. Co-crystal structure (2.7 Å) analysis of HD10 in complex with the PD-L1 protein revealed a strong affinity between the compound and the target PD-L1 dimer. This provides a solid theoretical basis for further in vitro and in vivo studies. Next, a typical cell-based experiment demonstrated that HD10 could remarkably prevent the interaction of hPD-1 293 T cells from human recombinant PD-L1 protein, effectively restoring T cell function, and promoting IFN-γ secretion in a dose-dependent manner. Moreover, HD10 was effective in suppressing tumor growth (TGI = 57.31 %) in a PD-1/PD-L1 humanized mouse model without obvious toxicity. Flow cytometry, qPCR, and immunohistochemistry data suggested that HD10 inhibits tumor growth by activating the immune system in vivo. Based on these results, it seems likely that HD10 is a promising clinical candidate that should be further investigated.

PubMed: 39032403
DOI: 10.1016/j.ejmech.2024.116683

Experimental method

X-RAY DIFFRACTION (2.7 Å)