Multidrug resistance (MDR) poses a significant challenge in anticancer treatments like chemotherapy, kinase inhibitors as well as in degrader-based therapies. In light of this, we aimed to explore the role of efflux transporters on the activity of FerroTAC degraders. A well-studied mechanism of MDR is indeed the enhanced export of drugs by ATP-binding cassette (ABC) efflux transporters, such as ABCB1/MDR1, ABCC1/MRP1, and ABCG2/BCRP. Recent evidence indicates that PROTACs might be substrates for the ABCB1/MDR1 efflux pump amongst others, suggesting that drug efflux could limit their intracellular availability and reduce their efficacy (Figure ). Unlike other transporters, ABC transporters are generally less restricted by substrate size and properties, recognising structurally and chemically unrelated hydrophobic and/or weakly amphipathic compounds. To investigate the effect of ABCB1/MDR1 efflux on FerroTACs, we conducted a HiBiT degradation assay with and without subtoxic concentrations of the ABCB1/MDR1 inhibitor, zosuquidar. Our results showed that a 1-hour pre-treatment with zosuquidar significantly enhanced the potency of both MZ1 and AS6 (Figure and). Specifically, AS6 exhibited 2-to 4.1-fold increase in DC50 for BRD2 and BRD3/4, while MZ1 showed up to a 5.7-fold increased DC50 for BRD2, suggesting that this class of MDR transporters limits the intracellular availability of MZ1 to a greater extend compared to AS6.