Val-Cit-PAB-OH is a peptide linker molecule used in the synthesis of drug conjugates.1,2,3,4,5 It is cleaved by cathepsin B, a protease highly expressed in cancer cells, which confers specificity of the drug conjugates to cancer cells.2 Val-Cit-PAB-OH has been used in the synthesis of antibody-drug conjugates (ADCs) containing the tubulin polymerization inhibitors KGP05 or monomethyl auristatin D (MMAD), as well as α-galactosylceramide or folic acid conjugates that target peptide antigens to natural killer T cells or exportin 1 (CRM1) inhibitors to cancer cells, respectively.1,3,4,5 It has also been used as a precursor in the synthesis of Mc-Val-Cit-PABC-PNP .1
1.Mondal, D., Ford, J., and Pinney, K.G.Improved methodology for the synthesis of a cathepsin B cleavable dipeptide linker, widely used in antibody-drug conjugate researchTetrahedron Lett.59(40)3594-3599(2018) 2.Dubowchik, G.M., Firestone, R.A., Padilla, L., et al.Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: Model studies of enzymatic drug release and antigen-specific in vitro anticancer activityBioconjug. Chem.13(4)855-869(2002) 3.Dorywalksa, M., Strop, P., Melton-Witt, J.A., et al.Effect of attachment site on stability of cleavable antibody drug conjugatesBioconjug. Chem.26(4)650-659(2015) 4.Anderson, R.J., Li, J., Kedzierski, L., et al.Augmenting influenza-specific T cell memory generation with a natural killer T cell-dependent glycolipid-peptide vaccineACS Chem. Biol.12(11)2898-2905(2017) 5.Klahn, P., Fetz, V., Ritter, A., et al.The nuclear export inhibitor aminoratjadone is a potent effector in extracellular-targeted drug conjugatesChem. Sci.10(20)5197-5210(2019)