IFITM proteins assist cellular uptake of diverse linked chemotypes

The search for cell-permeable drugs has conventionally focused on low-molecular weight (MW), nonpolar, 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), uptake of which was facilitated by IFITMs. We also found that IFITMs moderately assisted some proteolysis-targeting chimeras and examined the physicochemical requirements for involvement of this uptake pathway. Description Beyond traditional drug design Drug design prioritizes compounds likely to cross the cell membrane, leading to rules governing the size, polarity, and rigidity of chemical structures. However, there is increased interest in linking two chemotypes to allow greater selectivity for one target or to associate two targets. Lou et al. focused on a bitopic inhibitor, Rapalink-1, of the signaling protein mTOR that is active in vivo even though it is much too large to be considered drug like (see the Perspective by Lokey and Pye). The authors used chemical genetic approaches to show that the activity of Rapalink-1 depends on interferon-induced transmembrane proteins (IFITMs). They went on to show that IFITMs promote the cellular uptake of diverse linked chemotypes and to explore the role of linker length on the uptake pathway. This work may guide the development of bitopic drugs. —VV Chemical-genetic approaches elucidate the uptake pathway for molecules that break traditional drug design rules.