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

J Med Chem. 2019 May 9;62(9):4383-4400. doi: 10.1021/acs.jmedchem.8b01821. Epub 2019 Apr 30.

Abstract

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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors*
  • Cell Line, Tumor
  • Chlorophyll / analogs & derivatives
  • Chlorophyll / metabolism
  • Daunorubicin / pharmacology
  • Drug Resistance, Multiple / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Fluoresceins / metabolism
  • Humans
  • Irinotecan / pharmacology
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / antagonists & inhibitors*
  • Pyrimidines / pharmacology*
  • Pyrimidines / toxicity
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / toxicity
  • Thiophenes / pharmacology*
  • Thiophenes / toxicity

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Fluoresceins
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Pyrimidines
  • Small Molecule Libraries
  • Thiophenes
  • Chlorophyll
  • calcein AM
  • Irinotecan
  • pheophorbide a
  • multidrug resistance-associated protein 1
  • Daunorubicin