Discovery of the ((diaryl)methyl)phosphonic acid derivatives as novel CD73 inhibitors

Abstract

AbstractEcto‐nucleotidase CD73 inhibits immune function by overproducing adenosine. A series of important studies have shown that CD73 is over‐expressed in many cancers, and CD73 inhibitors are promising drugs for cancer (immunotherapy). Here, we describe the structure optimization of a hit compound obtained through screening an in‐house chemical library, (3‐(4‐(3‐aminophenyl)‐1H‐1,2,3‐triazol‐1‐yl)phenyl‐(naphthalen‐1‐yl)methyl)phosphonic acid (1). A series of ((diphenylmethyl) phosphonic acid) derivatives were synthesized, and all target compounds were characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). Then structure–activity relationship analysis using the in vitro enzymatic inhibition assay was performed, which led to the discovery of a number of compounds (11, 13, 14, 17, 19, 23, and 27) that exhibited greater inhibitory activity than the lead compound 1. Among them, the compounds 14 and 23, with p‐Cl and p‐ethyl substitution on the terminal phenyl ring respectively, showed the strongest inhibitory activity against CD73, with IC50 values of 2.35 and 2.55 μM respectively. And we believe that compounds 14 and 23 can serve as lead compounds for further research on specific CD73 inhibitors.