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 (Cay-14610) by an ultrashort linker. 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 (ALKF1174L) 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.Formal Name: 4-((2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. Molecular Formula: C39H40ClN9O8S. Formula Weight: 830.3. Purity: >95%. Formulation: (Request formulation change), A solid. Solubility: DMF: 30 mg/ml, DMSO: 30 mg/ml. SMILES: O=C(CNC1=C(C(N(C2C(NC(CC2)=O)=O)C3=O)=O)C3=CC=C1)N4CCN(C5=CC(OC)=C(NC6=NC(NC7=CC=CC=C7S(C(C)C)(=O)=O)=C(Cl)C=N6)C=C5)CC4. InChi Code: InChI=1S/C39H40ClN9O8S/c1-22(2)58(55,56)31-10-5-4-8-27(31)43-35-25(40)20-42-39(46-35)44-26-12-11-23(19-30(26)57-3)47-15-17-48(18-16-47)33(51)21-41-28-9-6-7-24-34(28)38(54)49(37(24)53)29-13-14-32(50)45-36(29)52/h4-12,19-20,22,29,41H,13-18,21H2,1-3H3,(H,45,50,52)(H2,42,43,44,46). InChi Key: MCCIEZLYIAJGSE-UHFFFAOYSA-N.