Identification of Thienopyrimidine Scaffold as an Inhibitor of the ABC Transport Protein ABCC1 (MRP1) and Related Transporters Using a Combined Virtual Screening Approach

A virtual screening protocol with
combination of similarity search
and pharmacophore modeling was applied to virtually screen a large
compound library to gain new scaffolds regarding ABCC1 inhibition.
Biological investigation of promising candidates revealed four compounds
as ABCC1 inhibitors, three of them with scaffolds not associated with
ABCC1 inhibition until now. The best hit moleculea thienopyrimidinewas
a moderately potent, competitive inhibitor of the ABCC1-mediated transport
of calcein AM which also sensitized ABCC1-overexpressing cells toward
daunorubicin. Further evaluation showed that it was a moderately potent,
competitive inhibitor of the ABCB1-mediated transport of calcein AM,
and noncompetitive inhibitor of the ABCG2-mediated pheophorbide A
transport. In addition, the thienopyrimidine could also sensitize
ABCB1- as well as ABCG2-overexpressing cells toward daunorubicin and
SN-38, respectively, in concentration ranges that qualified it as
one of the ten best triple ABCC1/ABCB1/ABCG2 inhibitors in the literature.
Besides, three more new multitarget inhibitors were identified by
this virtual screening approach.