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

Sophie E B Ambjørner1, Michael Wiese2, Sebastian Christoph Köhler2

  • 1Department of Drug Design and Pharmacology, University of Copenhagen, 1165 Copenhagen, Denmark.

Cells
|March 8, 2020
PubMed

Insights

A new drug candidate, SCO-201, effectively reverses cancer drug resistance mediated by breast cancer resistance protein (BCRP). This discovery offers potential for overcoming treatment failures caused by BCRP in cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • ATP-binding cassette (ABC) transporters, like breast cancer resistance protein (BCRP), are crucial in multidrug resistance (MDR), leading to chemotherapy failure.
  • Currently, no approved drugs effectively reverse BCRP-mediated drug resistance.
  • Developing strategies to overcome MDR is critical for improving cancer treatment outcomes.

Purpose of the Study:

  • To investigate the potential of a novel drug candidate, SCO-201, to inhibit BCRP.
  • To determine if SCO-201 can reverse BCRP-mediated resistance to anti-cancer drugs.
  • To assess the specificity and safety profile of SCO-201.

Main Methods:

  • In vitro cell viability assays using SN-38 resistant colon cancer cells and BCRP-overexpressing non-cancer cells.
  • Dye efflux assays, bidirectional transport assays, and ATPase assays to confirm BCRP inhibition.
  • In silico interaction analyses to elucidate the mechanism of inhibition.
  • In vitro drug metabolism and pharmacokinetic studies to evaluate off-target effects on cytochrome P450 (CYP) enzymes and other transporters.

Main Results:

  • SCO-201 demonstrated significant reversal of SN-38 resistance in BCRP-mediated resistant cancer models.
  • Functional assays confirmed that SCO-201 directly inhibits BCRP activity.
  • In silico analysis suggested SCO-201 competes with SN-38 at the BCRP drug-binding site.
  • SCO-201 exhibited high selectivity, inhibiting BCRP without affecting CYP enzymes or other transporters.

Conclusions:

  • SCO-201 is a potent inhibitor of BCRP.
  • SCO-201 effectively reverses BCRP-mediated drug resistance.
  • SCO-201 shows potential as a specific and safe therapeutic agent for overcoming BCRP-driven chemoresistance.
Keywords:
ATP-binding cassette transporterSCO-201breast cancer resistance protein (BCRP), ABCG2drug efflux pumpsmultidrug resistance in cancerpyrazolo-pyrimidine derivative

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