Overexpression of
ATP-binding cassette transporter superfamily G member 2 (ABCG2), is known as a major mechanism mediating multidrug resistance (MDR) in
cancer cells.
MLN7243 is a small-molecule
ubiquitin activating enzyme inhibitor currently under clinical investigation. The aim of the current study is to determine if
MLN7243 is a substrate of MDR-related
ABCG2 transporter. Our results showed that
cancer cells overexpressing
ABCG2 transporter were resistant to
MLN7243 compared to the parental cells, while knockout of ABCG2 gene or pharmacological inhibition of ABCG2 efflux function completely reversed the drug resistance. Unexpectedly, the endogenous low expression of ABCG2 is sufficient to confer
cancer cells resistance to
MLN7243. The ABCG2
ATPase assay and HPLC assay suggested that
MLN7243 can significantly stimulate ABCG2
ATPase activity and be pumped out from ABCG2-overexpressing cells by ABCG2. The docking analysis also implied that
MLN7243 binds to ABCG2
drug-binding pocket with optimal binding affinity. However,
MLN7243 did not competitively inhibit the efflux of other ABCG2 substrate drugs, indicating it may not serve as an MDR reversal agent. In conclusion, our study provides direct in vitro evidence to show that
MLN7243 is a potent ABCG2 substrate. If our results can be translated to humans, it suggests that combining
MLN7243 with ABCG2 inhibitors may enhance the anticancer efficacy for patients with high
tumor ABCG2 level.