Mechanistic Studies of the Multiple Myeloma and Melanoma Cell-Selective Toxicity of the Rpn13-Binding Peptoid KDT-11

Highlights

• Peptidomimetic KDT-11 induces cancer-selective G1/S cell-cycle arrest

• KDT-11 does not disrupt its reported target Rpn13's known protein interactions

• Cellular sensitivity to KDT-11 does not relate to Rpn13 protein level

Summary

We previously reported a peptoid ligand for the proteasomal ubiquitin receptor Rpn13 called KDT-11 and demonstrated that this compound is toxic to multiple myeloma cells, but not non-malignant cells. Here, we show that KDT-11 decreases the viability of a variety of cancer cell lines, especially melanomas and various blood cancers. The peptoid induces selective G1 cell-cycle arrest, resulting in eventual apoptosis. While KDT-11 does not antagonize any of the known protein-protein interactions involving Rpn13, the peptoid inhibits the ability of Rpn13 to stimulate the activity of an associated deubiquitylase Uch37/UCHL5 in vitro, suggesting a high level of Uch37 activity might be important for cancer cell proliferation. However, a variety of experiments in SK-MEL-5 melanoma cells suggest that KDT-11's cytotoxic effects are mediated by interactions with proteins other than Rpn13.