2. Academic Validation
  3. N-methylmorpholine incorporation into the structure of biphenyl leads to the bioactive inhibitor of PD-1/PD-L1 interaction

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

  • Bioorg Med Chem Lett. 2024 Sep 15:110:129882. doi: 10.1016/j.bmcl.2024.129882.
Julia Zaber 1,  Lukasz Skalniak 2,  Ganna P Gudz 2,  Aleksandra Hec-Gałązka 3,  Magdalena Zarnik 2,  Urszula Tyrcha 4,  Malgorzata Stec 5,  Maciej Siedlar 5,  Tad A Holak 6,  Tomasz Sitar 4,  Damian Muszak 7
Affiliations

Affiliations

  • 1 Jagiellonian University, Doctoral School of Exact and Natural Sciences, prof. S. Lojasiewicza 11, 30-348 Krakow, Poland; Jagiellonian University, Faculty of Chemistry, Department of Organic Chemistry, Gronostajowa 2, 30-387 Krakow, Poland.
  • 2 Jagiellonian University, Faculty of Chemistry, Department of Organic Chemistry, Gronostajowa 2, 30-387 Krakow, Poland.
  • 3 Jagiellonian University, Doctoral School of Exact and Natural Sciences, prof. S. Lojasiewicza 11, 30-348 Krakow, Poland; Jagiellonian University, Faculty of Chemistry, Department of Organic Chemistry, Gronostajowa 2, 30-387 Krakow, Poland; Recepton Sp. z o.o., ul. Trzy Lipy 3, 80-172 Gdansk, Poland.
  • 4 Recepton Sp. z o.o., ul. Trzy Lipy 3, 80-172 Gdansk, Poland.
  • 5 Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, Poland.
  • 6 Jagiellonian University, Faculty of Chemistry, Department of Organic Chemistry, Gronostajowa 2, 30-387 Krakow, Poland; Recepton Sp. z o.o., ul. Trzy Lipy 3, 80-172 Gdansk, Poland.
  • 7 Jagiellonian University, Faculty of Chemistry, Department of Organic Chemistry, Gronostajowa 2, 30-387 Krakow, Poland. Electronic address: damian.muszak@uj.edu.pl.
PMID: 38996937 DOI: 10.1016/j.bmcl.2024.129882
Abstract

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.

Keywords

Combination; Immune checkpoint blockade; PD-1; PD-L1; Small molecule.

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