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

## TL;DR

This paper introduces a new strategy to find drug candidates for hard-to-target membrane transporters by leveraging polypharmacology.

## Contribution

A novel approach using polypharmacology to identify hit molecules for undruggable ABC and SLC transporters.

## Key findings

- Polypharmacological drugs showed higher hit rates against polyspecific SLC transporters.
- Pranlukast was identified as a common substrate for multiple transporters.
- Privileged structures were found to mediate interactions between specific and polyspecific transporters.

## Abstract

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.