Targeted Delivery of Ubiquitin-Conjugated BH3 Peptide-Based Mcl-1 Inhibitors into Cancer Cells

摘要: BH3 peptides are key mediators of apoptosis and have served as the lead structures for development anticancer therapeutics. Previously, we reported application a simple cysteine-based side chain cross-linking chemistry to NoxaBH3 that led generation cross-linked with increased cell permeability higher inhibitory activity against Mcl-1 (Muppidi, A., Doi, K., Edwardraja, S., Drake, E. J., Gulick, A. M., Wang, H.-G., Lin, Q. (2012) J. Am. Chem. Soc. 134, 14734). To deliver selectively into cancer cells enhanced efficacy reduced systemic toxicity, here report conjugation extracellular ubiquitin, recently identified endogenous ligand CXCR4, chemokine receptor overexpressed in cells. The resulting ubiquitin-NoxaBH3 peptide conjugates showed selective killing CXCR4-expressing successful deliv...