N-methylmorpholine incorporation into the structure of biphenyl leads to the bioactive inhibitor of PD-1/PD-L1 interaction

• Published in: Bioorganic & medicinal chemistry letters 2024-09, Vol.110, p.129882, Article 129882
• Main Authors: Zaber, Julia, Skalniak, Lukasz, Gudz, Ganna P., Hec-Gałązka, Aleksandra, Zarnik, Magdalena, Tyrcha, Urszula, Stec, Malgorzata, Siedlar, Maciej, Holak, Tad A., Sitar, Tomasz, Muszak, Damian
• Format: Article
• Language: English
• Subjects: B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; Biphenyl Compounds - antagonists & inhibitors; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Combination; Dose-Response Relationship, Drug; Humans; Immune checkpoint blockade; Molecular Docking Simulation; Molecular Structure; Morpholines - chemical synthesis; Morpholines - chemistry; Morpholines - pharmacology; PD-1; PD-L1; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Small molecule; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129882

[Display omitted] •Utility of N-methylmorpholine derivatives as inhibitors of PD-L1 protein.•Optimal elongation path determination of N-methylmorpholine in the context of affinity to PD-L1.•Activity assessment in a biophysical and biological context.•Modeled interaction of the leading molecule with molecular target. We present new small-molecular probes targeting the human PD-L1 protein. The molecules were designed by incorporating a newly discovered N-methylmorpholine substituent into a known biphenyl-based structure. Four prototype derivatives of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (STD4), comprising a morpholine substituent fused with a biphenyl core at different orientations were first verified for their potential binding to PD-L1 using the molecular docking method. A more favorable 7-phenyl derivative of STD4 was then equipped with an amide bond, pyridine, and either a tris(hydroxymethyl)aminomethane or serinol tail leading to two final molecules. Among them, compound 1c showed activity in three bioassays, i.e., the homogenous time-resolved fluorescence (HTRF) assay, immune checkpoint blockade (ICB) assay, and T-cell activation (TCA) assay. Our work shows that morpholine can substitute for dioxane and becomes a promising component in PD-L1-targeting molecules. This finding unlocks new avenues for optimizing PD-L1-targeting compounds, presenting exciting prospects for future developments in this field.