AP-1

AP-1 is a miniaturized proteolysis-targeting chimera (PROTAC) that contains an anaplastic lymphoma kinase (ALK) ligand connected to the E3 ubiquitin ligase ligand (±)-thalidomide by an ultrashort linker.¹ It degrades the ALK fusion protein NPM-ALK in Karpas-299 cells, where it is highly expressed, when used at concentrations ranging from 10 to 300 nM, an effect that can be blocked by the proteasome inhibitor MG-132. It also degrades the ALK fusion protein EML4-ALK and ALK containing the phenylalanine-to-leucine substitution mutation at position 1174 (ALK^F1174L) expressed in SN-N-SH and NCI H3122 cells, respectively. AP-1 is cytotoxic to ALK-dependent Karpas-299 cells (IC₅₀ = 0.1265 nM) but not non-ALK-dependent THP-1 cells (IC₅₀ = 2,704 nM). It reduces tumor volume in an NCI H3122 mouse xenograft model when administered at doses of 25, 50, and 100 mg/kg.