Selective Efflux Inhibition of ATP-binding Cassette Sub-family G Member 2 Academic Article Book uri icon


  • Although many mechanisms exist, resistance of tumors to cancer therapy drugs is the principal reason for treatment failure and the majority of clinical and experimental data indicates that multidrug transporters such ABCB1 (a.k.a. Pgp, MDR1) and ABCG2 (a.k.a. BCRP, MRP1) play a leading role by preventing cytotoxic intracellular drug concentrations. Inhibition of the function of these drug efflux pumps presents a promising approach to treat cancer using existing drugs. To date, clinical trials with such adjuvant therapies have been relatively unsuccessful. One likely contributing factor to these failed clinical applications is limited understanding of specific substrate/inhibitor/pump interactions. We propose that searching for selective efflux inhibitors by profiling multiple ABC transporter efflux pumps against a library of small molecules could result in molecular probes that could further explore such interactions. Using the mitochondrial membrane potential dye JC-1 as a dual-pump fluorescent reporter substrate in our primary screening protocol we observed a piperazine substituted pyrazolo[1,5-a]pyrimidine substructure with promise for selective efflux inhibition. As a result of a focused structure activity relationship (SAR) driven chemistry effort we describe herein a selective ABCG2 efflux inhibitor (SID 88095709) with a 36 fold preference over ABCB1 with increased activity over prior art for ABCG2. The probe has low in vitro cellular toxicity, as well as adequate solubility and stability under appropriate experimental conditions. The probe also appears to have an IP landscape with space to operate. In vitro chemotherapeutic potentiation further illustrates the utility of the probe compound and related members. A related scaffold (SID 97301789) also shows promise for further development and optimization.

publication date

  • January 1, 2010