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Membrane permeability is a major challenge in drug development. Whilst most small molecules cross membranes by passive diffusion, the mechanisms mediating the cell permeability of larger linked chemotypes — used to engage challenging protein interfaces — remain poorly understood. Using a genome-wide CRISPR screen in patient-derived chronic myeloid leukemia cells, Lou et al. set out to identify proteins required for the activity of RapaLink-1, a high molecular weight (1800 Da) bitopic inhibitor of mammalian target of rapamycin (mTOR). RapaLink-1, comprised of the allosteric mTOR inhibitor rapamycin covalently attached to the active site inhibitor sapanisertib, displays potent cellular efficacy and is able to penetrate the blood–brain barrier. The screen revealed a strong chemical–genetic relationship between the cellular efficacy of RapaLink-1 and the expression of interferon-induced transmembrane proteins (IFITMs). Furthermore, the sensitivity of hundreds of cell lines to RapaLink-1 was highly correlated to IFITM expression. The potency of other designed bitopic molecules, namely DasatiLink-1 (dasatinib combined with asciminib, targeting BCR-ABL1) and BisRoc-1 (a cross-linked dimer of rocaglamide, targeting EIF4A1) was also significantly enhanced by IFITM expression.