The Pyrazolo[3,4-d]pyrimidine Derivative, SCO-201, Reverses Multidrug Resistance Mediated by ABCG2/BCRP.

Cells
Sophie E B AmbjørnerJan Stenvang

Abstract

ATP-binding cassette (ABC) transporters, such as breast cancer resistance protein (BCRP), are key players in resistance to multiple anti-cancer drugs, leading to cancer treatment failure and cancer-related death. Currently, there are no clinically approved drugs for reversal of cancer drug resistance caused by ABC transporters. This study investigated if a novel drug candidate, SCO-201, could inhibit BCRP and reverse BCRP-mediated drug resistance. We applied in vitro cell viability assays in SN-38 (7-Ethyl-10-hydroxycamptothecin)-resistant colon cancer cells and in non-cancer cells with ectopic expression of BCRP. SCO-201 reversed resistance to SN-38 (active metabolite of irinotecan) in both model systems. Dye efflux assays, bidirectional transport assays, and ATPase assays demonstrated that SCO-201 inhibits BCRP. In silico interaction analyses supported the ATPase assay data and suggest that SCO-201 competes with SN-38 for the BCRP drug-binding site. To analyze for inhibition of other transporters or cytochrome P450 (CYP) enzymes, we performed enzyme and transporter assays by in vitro drug metabolism and pharmacokinetics studies, which demonstrated that SCO-201 selectively inhibited BCRP and neither inhibited nor induced CYPs....Continue Reading

References

Jan 26, 1996·The Journal of Biological Chemistry·M MüllerB Sarkadi
May 20, 1999·Annual Review of Pharmacology and Toxicology·S V AmbudkarM M Gottesman
Jul 5, 2001·Biochemical and Biophysical Research Communications·C OzvegyB Sarkadi
Jan 31, 2002·Annual Review of Medicine·Michael M Gottesman
Mar 21, 2002·Nature Reviews. Cancer·Michael M GottesmanSusan E Bates
Oct 9, 2002·Medicinal Research Reviews·Erik De Clercq
Oct 8, 2003·The Oncologist·Gregory D LeonardSusan E Bates
Oct 25, 2003·Oncogene·Tito Fojo, Susan Bates
Mar 17, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Peter L GreenbergJacob M Rowe
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Mar 19, 2004·Journal of Medicinal Chemistry·Thomas A HalgrenJay L Banks
Apr 13, 2004·The Journal of Pharmacology and Experimental Therapeutics·Susan E BatesYves Pommier
May 29, 2004·FEBS Letters·Balázs SarkadiAndrás Váradi
Nov 10, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Paula M FracassoJan H M Schellens
Mar 7, 2006·Nature Reviews. Drug Discovery·Gergely SzakácsMichael M Gottesman
Mar 8, 2006·Anti-cancer Drugs·Abdelhakim Ahmed-BelkacemAttilio Di Pietro
Feb 27, 2007·Cancer Metastasis Reviews·Robert W RobeySusan E Bates
Feb 6, 2008·Expert Opinion on Drug Metabolism & Toxicology·Suneet ShuklaSuresh V Ambudkar
Jun 27, 2008·Cellular and Molecular Life Sciences : CMLS·H Lage
Aug 6, 2008·Bioorganic & Medicinal Chemistry·Anne PickMichael Wiese
May 7, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jame AbrahamTito Fojo
Jan 16, 2010·Nature Reviews. Cancer·Jamie I FletcherMurray D Norris
Nov 18, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ronan J KellySusan E Bates
Apr 13, 2012·Expert Opinion on Investigational Drugs·Marco Falasca, Kenneth J Linton
Apr 13, 2013·Journal of Computer-aided Molecular Design·G Madhavi SastryWoody Sherman
Feb 14, 2014·Pharmacogenomics and Personalized Medicine·Kohji NoguchiYoshikazu Sugimoto
Jan 19, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Stine Ninel HansenAnne-Sofie Schrohl
Jul 8, 2015·The Journal of Pharmacology and Experimental Therapeutics·Lora D WeidnerMatthew D Hall
Aug 12, 2015·ChemMedChem·Vadim A MakarovMichaela Schmidtke
Jan 12, 2016·Therapeutic Advances in Medical Oncology·William A HammondKabir Mody
Jul 28, 2016·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Wen LiZhe-Sheng Chen

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Methods Mentioned

BETA
Assay
fluorescence microscopy
glycosylation
imaging cytometry

Software Mentioned

VisionWorks
PyMOL Molecular Graphics System
Ligprep
GraphPad Prism
Schrödinger
Simulations
Protein Preparation Wizard

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