9QSM

small molecule inhibitor in complex with PD-L1

This is a non-PDB format compatible entry.

Summary for 9QSM

• Entry DOI: 10.2210/pdb9qsm/pdb
• Descriptor: Programmed cell death 1 ligand 1, ~{N}-[2-chloranyl-3-[2-chloranyl-3-[4-[[[2-(hydroxymethyl)-1,3-bis(oxidanyl)propan-2-yl]amino]methyl]-3-methoxy-phenyl]phenyl]phenyl]-5-[[[2-(hydroxymethyl)-1,3-bis(oxidanyl)propan-2-yl]amino]methyl]pyridine-2-carboxamide (3 entities in total)
• Functional Keywords: pd-l1, small molecule inhibitors, immune checkpoint, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 90219.41

Authors

Muszak, D.,Kocik-Krol, J.,Zaber, J.,Kruc, O.,Palej, U.,Fijolkowska, K.,Maslanka, A.,Magiera-Mularz, K.,Plewka, J.,Stec, M.,Siedlar, M.,Musielak, B.,Kitel, R.,Skalniak, L.,Surmiak, E. (deposition date: 2025-04-05, release date: 2026-02-18, Last modification date: 2026-02-25)

Primary citation

Muszak, D.,Kocik-Krol, J.,Zaber, J.,Kruc, O.,Palej, U.,Fijolkowska, K.,Maslanka, A.,Magiera-Mularz, K.,Plewka, J.,Stec, M.,Surmiak, M.,Szafarz, M.,Siedlar, M.,Musielak, B.,Kitel, R.,Wyska, E.,Skalniak, L.,Surmiak, E.
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., 307:118652-118652, 2026

PubMed 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.

PubMed: 41691995
DOI: 10.1016/j.ejmech.2026.118652

Experimental method

X-RAY DIFFRACTION (1.75 Å)