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

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

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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