Progress on biphenyl derivatives as PD-1/PD-L1 inhibitors

Wang, Shurong; Wang, Yuli; Yan, Hong

doi:10.1007/s00044-023-03127-6

Cited by 3 publications

(4 citation statements)

References 49 publications

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“…Skalniak et al demonstrated, by NMR studies, that starting from BMS-1166, the minimum fragmentconserving activity is the biphenyl group (Figure 2) [32]. Many reviews published so far have focused on PD-L1 ligands [33][34][35][36][37][38][39]. A very recent review revised the application of computational methods to the discovery of PD-1/PD-L1 inhibitors [40].…”

Section: Small Molecule Binders Of Pd-l1mentioning

confidence: 99%

“…In addition, the application of in silico methods to the identification of new compounds through virtual screening campaigns was explored. Many reviews published so far have focused on PD-L1 ligands [33][34][35][36][37][38][39]. A very recent review revised the application of computational methods to the discovery of PD-1/PD-L1 inhibitors [40].…”

Section: Small Molecule Binders Of Pd-l1mentioning

confidence: 99%

“…Many reviews published so far have focused on PD-L1 ligands [ 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. A very recent review revised the application of computational methods to the discovery of PD-1/PD-L1 inhibitors [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

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A Comprehensive Computational Insight into the PD-L1 Binding to PD-1 and Small Molecules

Fantacuzzi,

Paciotti,

Agamennone

2024

Pharmaceuticals

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Immunotherapy has marked a revolution in cancer therapy. The most extensively studied target in this field is represented by the protein–protein interaction between PD-1 and its ligand, PD-L1. The promising results obtained with the clinical use of monoclonal antibodies (mAbs) directed against both PD-1 and PD-L1 have prompted the search for small-molecule binders capable of disrupting the protein–protein contact and overcoming the limitations presented by mAbs. The disclosure of the first X-ray complexes of PD-L1 with BMS ligands showed the protein in dimeric form, with the ligand in a symmetrical hydrophobic tunnel. These findings paved the way for the discovery of new ligands. To this end, and to understand the binding mechanism of small molecules to PD-L1 along with the dimerization process, many structure-based computational studies have been applied. In the present review, we examined the most relevant articles presenting computational analyses aimed at elucidating the binding mechanism of PD-L1 with PD-1 and small molecule ligands. Additionally, virtual screening studies that identified validated PD-L1 ligands were included. The relevance of the reported studies highlights the increasingly prominent role that these techniques can play in chemical biology and drug discovery.

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Section: Small Molecule Binders Of Pd-l1mentioning

confidence: 99%

Section: Small Molecule Binders Of Pd-l1mentioning

confidence: 99%

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A Comprehensive Computational Insight into the PD-L1 Binding to PD-1 and Small Molecules

Fantacuzzi,

Paciotti,

Agamennone

2024

Pharmaceuticals

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“…Encouraged by the promising bioactivity of short terphenyl molecules described previously by us [ 36 , 37 ], and others [ 38 , 39 ] we decided to explore further the terphenyl scaffold. Considering the high affinity towards PD-L1 demonstrated by symmetric Compound A, as well as the general trend observed for the longer, symmetric inhibitors, we designed a series of C2-symmetrical terphenyl compounds SMIs that support further investigation on the terphenyl derivatives symmetry impact on binding modes to the PD-L1 protein.…”

Section: Introductionmentioning

confidence: 99%

C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand 1 Protein–Protein Interaction

Klimek,

Kruc,

Ceklarz

et al. 2024

Molecules

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The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the PD-1/PD-L1 axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting PD-1/PD-L1 are monoclonal antibody-based drugs, which have several limitations. Therefore, small molecule compounds are emerging as an attractive alternative that can potentially overcome the drawbacks of mAb-based therapy. In this article, we present a novel class of small molecule compounds based on the terphenyl scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an m-terphenyl core, an additional aromatic ring, and a solubilizing agent. Using molecular docking, we designed a series of final compounds, which were subsequently synthesized and tested in HTRF assay and NMR binding assay to evaluate their activity. In addition, we performed an in-depth analysis of the mutual arrangement of the phenyl rings of the terphenyl core within the binding pocket of PD-L1 and found several correlations between the plane angle values and the affinity of the compounds towards the protein.

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Computational analysis of PD-L1 dimerization mechanism induced by small molecules and potential dynamical properties

Xu,

Luo,

Zhao

et al. 2024

International Journal of Biological Macromolecules

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Progress on biphenyl derivatives as PD-1/PD-L1 inhibitors

Cited by 3 publications

References 49 publications

A Comprehensive Computational Insight into the PD-L1 Binding to PD-1 and Small Molecules

A Comprehensive Computational Insight into the PD-L1 Binding to PD-1 and Small Molecules

C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand 1 Protein–Protein Interaction

Computational analysis of PD-L1 dimerization mechanism induced by small molecules and potential dynamical properties

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