Tariquidar-related triazoles as potent, selective and stable inhibitors of ABCG2 (BCRP)

Eur J Med Chem. 2020 Apr 1;191:112133. doi: 10.1016/j.ejmech.2020.112133. Epub 2020 Feb 10.


Tariquidar derivatives have been described as potent and selective ABCG2 inhibitors. However, their susceptibility to hydrolysis limits their applicability. The current study comprises the synthesis and characterization of novel tariquidar-related inhibitors, obtained by bioisosteric replacement of the labile moieties in our previous tariquidar analog UR-ME22-1 (9). CuAAC ("click" reaction) gave convenient access to a triazole core as a substitute for the labile amide group and the labile ester moiety was replaced by different acyl groups in a Sugasawa reaction. A stability assay proved the enhancement of the stability in blood plasma. Compounds UR-MB108 (57) and UR-MB136 (59) inhibited ABCG2 in a Hoechst 33342 transport assay with an IC50 value of about 80 nM and belong to the most potent ABCG2 inhibitors described so far. Compound 57 was highly selective, whereas its PEGylated analog 59 showed some potency at ABCB1. Both 57 and 59 produced an ABCG2 ATPase-depressing effect which is in agreement with our precedent cryo-EM study identifying 59 as an ATPase inhibitor that exerts its effect via locking the inward-facing conformation. Thermostabilization of ABCG2 by 57 and 59 can be taken as a hint to comparable binding to ABCG2. As reference substances, compounds 57 and 59 allow additional mechanistic studies on ABCG2 inhibition. Due to their stability in blood plasma, they are also applicable in vivo. The highly specific inhibitor 57 is suited for PET labeling, helping to further elucidate the (patho)physiological role of ABCG2, e.g. at the BBB.

Keywords: ABCG2 transporter; ATPase; BCRP; Hoechst33342; Inhibitors; Multidrug resistance.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • KB Cells
  • MCF-7 Cells
  • Molecular Structure
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism
  • Quinolines / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*
  • Tumor Cells, Cultured


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Neoplasm Proteins
  • Quinolines
  • Triazoles
  • tariquidar