Nonsymmetrically Substituted 1,1'-Biphenyl-Based Small Molecule Inhibitors of the PD-1/PD-L1 Interaction

  • ACS Med Chem Lett. 2024 Jun 3;15(6):828-836. doi: 10.1021/acsmedchemlett.4c00042.
Aleksandra Hec-Gałązka  1  2  3 ,  Urszula Tyrcha  3 ,  Jan Barczyński  3 ,  Przemyslaw Bielski  1  2  3 ,  Michał Mikitiuk  3 ,  Ganna P Gudz  2 ,  Radosław Kitel  2 ,  Bogdan Musielak  2 ,  Jacek Plewka  2 ,  Tomasz Sitar  3 ,  Tad A Holak  3
Affiliations
  • 1. Jagiellonian University, Doctoral School of Exact and Natural Sciences, prof. S. Łojasiewicza 11, 30-348 Krakow, Poland.
  • 2. Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.
  • 3. Recepton Sp. z o.o., ul. Trzy Lipy 3, 80-172 Gdansk, Poland.
PMID: 38894909 DOI: 10.1021/acsmedchemlett.4c00042
Abstract

Therapeutic antibodies directed against either programmed cell death-1 protein (PD-1) or its ligand PD-L1 have demonstrated efficacy in the treatment of various cancers. In contrast with antibodies, small molecules have the potential for increased tissue penetration; better pharmacology; and therefore, improved antitumor activity. A series of nonsymmetric C2 inhibitors were synthesized and evaluated for PD-1/PD-L1 interaction inhibition. These compounds induced PD-L1 dimerization and effectively blocked PD-L1/PD-1 interaction in a homogeneous time-resolved fluorescence (HTRF) assay with most inhibitors exhibiting IC50 values in the single-digit nM range and below. Their high inhibitory potency was also demonstrated in a cell-based coculture PD-1 signaling assay where 2 exhibited an EC50 inhibitory activity of 21.8 nM, which approached that of the PD-L1 antibody durvalumab (EC50 = 0.3-1.8 nM). Structural insight into how these inhibitors interact with PD-L1 was gained by using NMR and X-ray cocrystal structure studies. These data support further preclinical evaluation of these compounds as antibody alternatives.

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