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

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 IC 50 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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