Selective Efflux Inhibition of ATP-binding Cassette Sub-family G Member 2

Authors

J. Jacob Strouse, University of New Mexico
Irena Ivnitski-Steele, University of New Mexico
Hadya M. Njus, Cancer Research and Treatment Center
Terry D. Foutz, University of New Mexico
Tuanli Yao, University of Kansas
Warren S. Weiner, University of Kansas
Chad E. Schroeder, University of Kansas
Denise S. Simpson, Cedarville UniversityFollow
Brooks E. Maki, University of Kansas
Kelin Li, University of Kansas
Jennifer E. Golden, University of Kansas
Anna Waller, University of New Mexico
Annette E. Evangelisti, University of New Mexico
Susan M. Young, University of New Mexico
Dominique Perez, University of New Mexico
Stephanie E. Chavez, University of New Mexico
Mattew J. Garcia, University of New Mexico
Oleg Ursu, University of New Mexico
Dan C. Fara, University of New Mexico
Cristian G. Bologa, University of New Mexico
Mark Carter, University of New Mexico
Virginia M. Salas, University of New Mexico
George P. Tegos, University of New Mexico
Tudor Oprea, University of New Mexico
Bruce S. Edwards, University of New Mexico
Richard S. Larson, Cancer Research and Treatment Center
Jeffrey Aubé, University of Kansas
Larry A. Sklar, University of New Mexico

Document Type

Web Publication

Publication Date

2013

PubMed ID

23658968

Abstract

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.

Keywords

Inhibitors, cancer therapy, tumor, ATP

Comments

In Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information, 2013.

Recommended Citation

Strouse, J. Jacob; Ivnitski-Steele, Irena; Njus, Hadya M.; Foutz, Terry D.; Yao, Tuanli; Weiner, Warren S.; Schroeder, Chad E.; Simpson, Denise S.; Maki, Brooks E.; Li, Kelin; Golden, Jennifer E.; Waller, Anna; Evangelisti, Annette E.; Young, Susan M.; Perez, Dominique; Chavez, Stephanie E.; Garcia, Mattew J.; Ursu, Oleg; Fara, Dan C.; Bologa, Cristian G.; Carter, Mark; Salas, Virginia M.; Tegos, George P.; Oprea, Tudor; Edwards, Bruce S.; Larson, Richard S.; Aubé, Jeffrey; and Sklar, Larry A., "Selective Efflux Inhibition of ATP-binding Cassette Sub-family G Member 2" (2013). Pharmaceutical Sciences Faculty Publications. 158.
https://digitalcommons.cedarville.edu/pharmaceutical_sciences_publications/158