2. Academic Validation
  3. Design, synthesis, and evaluation of PD-1/PD-L1 small-molecule inhibitors bearing a rigid indane scaffold

Design, synthesis, and evaluation of PD-1/PD-L1 small-molecule inhibitors bearing a rigid indane scaffold

  • Eur J Med Chem. 2023 Aug 5;256:115468. doi: 10.1016/j.ejmech.2023.115468.
Shi Cai 1,  Kaizhen Wang 1,  Zhihao Qi 1,  Ke Ye 1,  Xinyuan Zhou 1,  Sheng Jiang 1,  Kuojun Zhang 2,  Xiangyu Zhang 3,  Tianyu Wang 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 3 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 4 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
PMID: 37207535 DOI: 10.1016/j.ejmech.2023.115468
Abstract

Discovery of small-molecule inhibitors against programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis provides a promising alternative to overcome the inevitable defects of PD-1/PD-L1 monoclonal Antibodies (mAbs). Here, we report a series of indanes as novel small-molecule inhibitors of PD-1/PD-L1 interaction. Thirty-one indanes were synthesized and the structure-activity relationships (SARs) demonstrated that conformational restriction with (S)-indane is superior in potency to inhibit the interaction of PD-1 and PD-L1. Compound D3 was found to be the most potent inhibitor with an IC50 value of 2.2 nM against PD-1/PD-L1 interaction. Cell-based assay showed that D3 significantly induced immune activity of peripheral blood mononuclear cells (PBMCs) against MDA-MB-231 cells and could restore the immune function of T cells by promoting secretion of the IFN-γ. The above results indicate that compound D3 is a promising PD-1/PD-L1 inhibitor that deserves further development.

Keywords

Cancer immunotherapy; Immune checkpoint blockade; PD-1/PD-L1; Small molecular inhibitors.

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