Discovery of Potent and Selective Inhibitors for ADAMTS‑4 through DNA-Encoded Library Technology (ELT)

The aggrecan degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. Here, we use DNA-encoded Library Technology (ELT) to identify novel ADAMTS-4 inhibitors from a DNA-encoded triazine library by affinity selection. Structure–activity relationship studies based on the selection information led to the identification of potent and highly selective inhibitors. For example, 4-(((4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2­(1H)-yl)-6-(((4-methylpiperazin-1-yl)­methyl)­amino)-1,3,5-triazin-2-yl)­amino)­methyl)-N-ethyl-N-(m-tolyl)­benzamide has IC50 of 10 nM against ADAMTS-4, with >1000-fold selectivity over ADAMT-5, MMP-13, TACE, and ADAMTS-13. These inhibitors have no obvious zinc ligand functionality.