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.
- 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].
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.
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target: PD-1/PD-L1Research Areas: Cancer
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