Target Class Repurposing Across Membrane Transporter Families Provides Privileged Ligands to Address Specific and Undruggable Pharmacological Targets.

Altogether, 60-70% of the ATP-binding cassette (ABC) and solute carrier (SLC) transporters can currently not be targeted by drugs, despite their involvement in human diseases. The design of potential drug candidates relies on hit identification and subsequent optimization with regard to selectivity and specificity. However, these workflows ultimately fail if no hit molecules can be found. We pursued a strategy of rational discovery of hit molecules for 'undruggable' ABC and SLC transporters based on polypharmacology as an alternative approach in the drug development repertoire. The 42 most polypharmacological ABC transporter modulators were profiled against eight specific (NAT, DAT, and SERT) and polyspecific (OCT1-3, MATE1-2K) SLCs. The general hit rate increased expectedly with the degree of polyspecificity, ranging from 0 to 9.52% (NAT, DAT, SERT) to 19.0-52.4% (OCT1-3, MATE1-2K). Striking was the hit rate for potent drugs, which was highest for the specific transporter SERT (75.0%); additionally, pranlukast (PRA) could also be identified as common substrate of NAT, DAT, SERT, and MATE2K. The polypharmacology of drugs correlated with their potency, and a higher degree of polypharmacology against ABCs was reflected in a higher degree of polypharmacology against SLCs. Some compounds mediated between both specific and polyspecific transporters which could be underpinned by the identification of common molecular features ('privileged structures'). The polypharmacology of selected drugs could be transferred to ABCA1 and Oatp1d1, two transporters for which almost no modulators have been reported before. This strategy provided privileged ligands with high potency at high hit rates to challenge transporter undruggability.