Optimizing Dimer Linker Length of an Anti-Cancer Peptoid Drug-Lead

Many recurrent tumors are caused by small subset of cells called cancer stem cells (CSCs), the especially aggressive portion of the tumor. Because CSCs self-renew and metastasize easily, drugs that are designed to kill cancer cells often miss them, causing cancer relapse due to CSC drug resistance. H358 is a non-small cell lung cancer (NSCLC) cell line that contains CSCs with the cell surface protein plectin. In previous studies, plectin has been shown to be an effective drug target for the peptoid PCS2, a compound that has since been modified to create the peptoid dimer PCS2D1. In this study, we used MTS assays to compare the effect of PCS2D1 to that of ten of its linker variations on the viability of H358 cells in hopes of finding some correlation between the peptoid activity and the length of the linker that connects the two monomers in the peptoid dimer. We studied linker lengths that ranged from two to eighty-five carbon atoms and found that PCS2D1’s linker length of four carbons allowed it to show optimal activity, while the modified compounds with shorter or longer linkers had less of an effect on the cells. With increased knowledge of how linker length affects cell killing activity, we have a better understanding of the characteristics required in a compound that targets plectin on H358 cells.