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Design of c-MET degraders based upon c-MET inhibitor tepotinib and CRBN ligand thalidomide. (A–B) The co-crystal structure of tepotinib with c-MET (PDB ID: 4R1V). (C) Structure of tepotinib and compound 6. (D) The binding affinities (Kd) to c-MET and IC50 of tepotinib and compound 6 in EBC-1 and Hs746T cells. The Kd determinations were performed in a competitive binding assay in triplicate. Data shown are mean ± SD of triplicate measurements. (E) Design of c-MET PROTACs.
