9-Deazapurines as Broad-Spectrum Inhibitors of the ABC Transport Proteins P-Glycoprotein, Multidrug Resistance-Associated Protein 1, and Breast Cancer Resistance Protein

Abstract

P-Glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2) are the three major ABC transport proteins conferring resistance to many structurally diverse anticancer agents, leading to the phenomenon called multidrug resistance (MDR). Much effort has been put into the development of clinically useful compounds to reverse MDR. Broad-spectrum inhibitors of ABC transport proteins can be of great use in cancers that simultaneously coexpress two or three transporters. In this work, we continued our effort to generate new, potent, nontoxic, and multiply effective inhibitors of the three major ABC transporters. The best compound was active in a very low micromolar concentration range against all three transporters and restored sensitivity toward daunorubicin (P-gp and MRP1) and SN-38 (BCRP) in A2780/ADR (P-gp), H69AR (MRP1), and MDCK II BCRP (BCRP) cells. Additionally, the compound is a noncompetitive inhibitor of daunorubicin (MRP1), calcein AM (P-gp), and pheophorbide A (BCRP) transport.

Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances

“…Our laboratory also synthesized and investigated indolopyrimidines . Although we did not succeed to find more potent compounds than 70 or 77, we found compounds with IC 50 values below 0.2 μM.…”

“…Our laboratory established the above‐stated compound 30 (in Ref. 463: compound 12) as standard inhibitor for biological investigation of MRP1‐overexpressing cells . In 2016, we found the cyclopropyl derivative 30 (Figure ) to be a highly selective MRP1 inhibitor, with IC 50 values of 0.247 μM (calcein AM) and 0.200 μM (daunorubicin) using H69AR cells.…”

“…Although the authors did not find a selective MRP1 inhibitor, it is noteworthy that a triple inhibitor of MRP1, P‐gp, and BCRP was found in low and submicromolar concentration range (compound 6r; IC 50 = 1.1 μM (H69AR, calcein AM); 0.3 μM (MES‐SA/Dx5, rhodamine 123); 0.2 μM (MES‐SA/MX2, Hoechst 33342; Figure )). This is up to now the most potent triple inhibitor of MRP1, P‐gp, and BCRP, although it was not analyzed whether sensitization occurs also at submicromolar concentrations, as shown by our working group …”

Recent advances in the search of BCRP- and dual P-gp/BCRP-based multidrug resistance modulators

“…Interestingly, some of the compounds were able to induce collateral sensitivity, but this effect was MRP1-dependent [170] . Also a series of more than 30 compounds bearing the 9-deazapurine scaffold [ Figure 20] were synthesized [171] , since it is a substructure present in pyrrolopyrimidines [172] and indolopyrimidines [173] which showed to be transporter inhibitors. Their inhibitory activity on P-gp, MRP1 and BCRP was measured: for P-gp, calcein AM efflux was evaluated in P-gp overexpressing A2780 adr cell line; for MRP1 the daunorubicin assay on H69AR overexpressing MRP1 cells (ATCC CRL-11351) was used; finally, the effect on BCRP was evaluated by the pheophorbide A assay on MDCK II BCRP cells which overexpress this protein.…”

An energy-blocking nanoparticle decorated with anti-VEGF antibody to reverse chemotherapeutic drug resistance

“…Therefore, many studies using NPs that can inhibit the function of ABC transporters to further overcome MDR have been reported. 18,19 Previous work has only focused on the ABC transporter itself, 20,21 but few strategies are reported through mitochondria to reverse MDR. In addition, it was well recognized that mitochondria is the energy-supplying center of cells and the regulatory center of apoptosis.…”