N-terphenylpicolinamide derivatives designed to target PD-L1 increase activation and proliferation of T cells, and their cytotoxic properties toward cancer cells

  • Eur J Med Chem. 2026 Apr 5:307:118652. doi: 10.1016/j.ejmech.2026.118652.
Damian Muszak  1 ,  Justyna Kocik-Krol  2 ,  Julia Zaber  3 ,  Oskar Kruc  3 ,  Urszula Palej  2 ,  Karolina Fijolkowska  2 ,  Agnieszka Maslanka  3 ,  Katarzyna Magiera-Mularz  2 ,  Jacek Plewka  2 ,  Malgorzata Stec  4 ,  Marcin Surmiak  5 ,  Malgorzata Szafarz  6 ,  Maciej Siedlar  4 ,  Bogdan Musielak  2 ,  Radoslaw Kitel  2 ,  Elzbieta Wyska  6 ,  Lukasz Skalniak  2 ,  Ewa Surmiak  7
Affiliations
  • 1. Jagiellonian University, Faculty of Chemistry, Department of Organic Chemistry, Gronostajowa 2, Krakow, 30-387, Poland. Electronic address: [email protected].
  • 2. Jagiellonian University, Faculty of Chemistry, Department of Organic Chemistry, Gronostajowa 2, Krakow, 30-387, Poland.
  • 3. Jagiellonian University, Faculty of Chemistry, Department of Organic Chemistry, Gronostajowa 2, Krakow, 30-387, Poland; Jagiellonian University, Doctoral School of Exact and Natural Sciences, prof. S. Lojasiewicza 11, Krakow, 30-348, Poland.
  • 4. Jagiellonian University Medical College, Institute of Pediatrics, Department of Clinical Immunology, Wielicka 265, Krakow, 30-663, Poland.
  • 5. Jagiellonian University Medical College, Bioengineering and Cell Imaging Laboratory, Center for the Development of Therapies for Civilization and Age-Related Diseases, Skawińska 8, Krakow, 31-066, Poland.
  • 6. Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacokinetics and Physical Pharmacy, Medyczna 9, Krakow, 30-688, Poland.
  • 7. Jagiellonian University, Faculty of Chemistry, Department of Organic Chemistry, Gronostajowa 2, Krakow, 30-387, Poland. Electronic address: [email protected].
PMID: 41691995 DOI: 10.1016/j.ejmech.2026.118652
Abstract

Programmed Cell Death Protein-1 (PD-1)/Programmed Cell Death-Ligand 1 (PD-L1) interaction has a crucial role in maintaining the immune system's self-tolerance by downregulating T cell activation. This mechanism is also used by several types of cancers. By overexpressing the PD-L1 protein, Cancer cells can evade the immune response and, therefore, become invisible to the immune system. Herein, we present a detailed characterization of the activity of improved N-terphenylpicolinamides, a class of small molecular blockers targeting the PD-L1 protein disclosed in our recent patent and following patent applications. In our studies, we utilized a cell-based structure-activity relationship (SAR) analysis, which allowed us to discriminate the bioactivity of molecules beyond the detection limits of the protein-based HTRF assay. Our final molecules display high affinity to the molecular target and in vitro bioactivity approaching the activity of a positive control ARB-272572 molecule. An optimized molecule activates primary immune cells, leading to enhanced elimination of Cancer cells, as we show in a newly developed co-culture setup. In addition, a co-crystal structure described here confirms the intended mode of binding of the small molecule to PD-L1. Our pharmacokinetics (PK) results rationalize the choice of a representative molecule for further in vivo testing.

Keywords
Cancer cells elimination; In vitro; PD-L1; Small molecule blocker; T cell activation.
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