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

• Published in: European journal of medicinal chemistry Vol. 191; p. 112133
• Main Authors: Antoni, Frauke, Bause, Manuel, Scholler, Matthias, Bauer, Stefanie, Stark, Simone A., Jackson, Scott M., Manolaridis, Ioannis, Locher, Kaspar P., König, Burkhard, Buschauer, Armin, Bernhardt, Günther
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.04.2020; Elsevier
• Subjects: ABCG2 transporter; ATPase; BCRP; Chemistry, Medicinal; Hoechst33342; Inhibitors; Life Sciences & Biomedicine; Multidrug resistance; Pharmacology & Pharmacy; Science & Technology; BCRP; VSSBUXPZPYVRTL-UHFFFAOYSA-N; CHAZSVOPUAINSR-UHFFFAOYSA-N; YIWXHIKHFPNMCO-UHFFFAOYSA-N; WRJQTHFUFBMEDE-UHFFFAOYSA-N; Multidrug resistance; ATPase; KQTJIUOOFLJRAY-UHFFFAOYSA-N; CRDPDHTUSFHKGC-UHFFFAOYSA-N; KFFZECZGHUCQAD-UHFFFAOYSA-N; FYCAGRIEHSHDTM-UHFFFAOYSA-N; ZYKLQXVIVRAEHZ-UHFFFAOYSA-N; Inhibitors; ABCG2 transporter; Hoechst33342; CELLS; TRANSPORTER; MODULATORS; DRUG-RESISTANCE; REVERSAL; IN-VITRO; MULTIDRUG-RESISTANCE; EXPRESSION; DERIVATIVES; CANCER RESISTANCE PROTEIN
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112133

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. [Display omitted] •Tariquidar-related ABCG2 inhibitors were synthesized and functionally characterized.•The compounds are among the most potent ABCG2 inhibitors described so far.•High selectivity for ABCG2 could be achieved.•Reduction of the ABCG2 ATPase activity was identified as one inhibition mechanism.•Stability in blood plasma was proven.