IFITM proteins assist cellular uptake of diverse linked chemotypes

The search for cell permeable drugs has conventionally focused on low molecular weight, non-polar, and rigid chemical structures. However, emerging therapeutic strategies break traditional drug design rules by employing flexibly linked chemical entities composed of more than one ligand. Using complementary genome-scale chemical-genetic approaches we identified an endogenous chemical uptake pathway involving interferon induced transmembrane proteins (IFITMs) that modulates the cell permeability of a prototypical biopic inhibitor of MTOR (RapaLink-1, MW: 1784 g/mol). We devised additional linked inhibitors targeting BCR-ABL1 (DasatiLink-1, MW: 1518 g/mol) and EIF4A1 (BisRoc-1, MW: 1466 g/mol) whose uptake was facilitated by IFITMs. We also found that IFITMs moderately assisted some proteolysis targeting chimeras (PROTACs) and examined the physicochemical requirements for involvement of this uptake pathway.