Discovery of a potent, selective, and covalent ZAP-70 kinase inhibitor

We report herein the structure-guided development of the first potent and covalent inhibitor of ZAP-70 kinase domain. In particular, compound 18 (RDN009) showed good selectivity for ZAP-70 over structurally related Syk, and displayed potent inhibitory effects on T cell proliferation, activation, and inflammatory cytokine production. A mass spectrometry analysis further confirmed the covalent linkage between the inhibitor and ZAP-70 protein at C346. Overall, the covalent inhibitor RDN009 represents a potent and selective probe of ZAP-70 for further development for treatment of autoimmune diseases.PMID:33845236 | DOI:10.1016/j.ejmech.2021.113393
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Source Type: research