The use of ubiquitin as a carrier for pro-apoptotic BH3 stapled peptides and chemotherapy drugs into CXCR4-overexpressing cancer cells
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The BH3 domain of BCL-2 family proteins plays a critical role in regulating the mitochondrial apoptotic pathway in multicellular organisms. Not surprisingly, there has been a surge of recent interest in preparing biologics utilizing the BH3 peptide for the development of potential anticancer therapeutics. Previously, our research group reported the preparation and targeted delivery of the NOXA-BH3-Ub K48R/K63R peptide conjugate into CXCR4-positive cancer cells. Although high inhibitory activity ( K i = 0.7 ± 0.2 nM) was observed, we sought to improve this activity profile and to further explore the utility of ubiquitin as a delivery vehicle for pro-apoptotic BH3 peptides. We, therefore, prepared several novel analogues of the previously reported peptide conjugate; however, in vitro study results did not show any improvements in inhibitory activity with the new peptide conjugates assessed in this study. We also made attempts to investigate the cellular activity of ubiquitin-conjugated chemotherapeutics against CXCR4-overexpressing cancer cells. Although the ubiquitin-drug conjugation chemistry proved to be successful, issues with solubility and product instability has prevented us from obtaining favorable results in subsequent cell-based assays.