Related Experiment Video

Updated: Aug 16, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

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2-Carboranylquinazoline: The Path to an ABCG2 Inhibitor

Philipp Stockmann1, Lydia Kuhnert2, Lisa Zörner1

  • 1Institute of Inorganic Chemistry Faculty of Chemistry and Mineralogy, Universität Leipzig, Johannisallee 29, 04103, Leipzig, Germany.

Chemmedchem
|March 29, 2023
PubMed

Insights

A novel hybrid molecule inhibits the breast cancer resistance protein (BCRP, ABCG2), a key factor in multidrug resistance. This compound effectively reverses chemotherapy resistance in cancer cells without causing toxicity, offering a promising new strategy for cancer treatment.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Pharmacology

Background:

  • Multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters, such as the breast cancer resistance protein (BCRP, ABCG2), significantly challenges anti-cancer therapy efficacy.
  • Cancer cells utilize efflux transporters like BCRP to secrete chemotherapeutic agents, reducing drug effectiveness.

Purpose of the Study:

  • To design and evaluate a novel inorganic-organic hybrid inhibitor targeting the BCRP transporter.
  • To investigate the potential of a carborane-modified quinazoline scaffold in overcoming BCRP-mediated drug resistance.

Main Methods:

  • Synthesis of an N-phenyl-2-carboranylquinazolin-4-amine hybrid molecule (compound 8).
  • Assessment of inhibitory activity against human BCRP (hABCG2).
  • Evaluation of drug resistance reversal in MDCKII-hABCG2 cells using a BCRP substrate (mitoxantrone) and determination of IC50 values.

Main Results:

  • Compound 8 demonstrated enhanced inhibitory activity against hABCG2 compared to its regioisomer.
  • The carboranylquinazoline 8 effectively reversed hABCG2-mediated mitoxantrone resistance in MDCKII-hABCG2 cells.
  • Compound 8 exhibited low micromolar toxicity, similar to the reference inhibitor Ko143.

Conclusions:

  • Compound 8 represents a promising scaffold for developing new BCRP inhibitors.
  • The strategic incorporation of a carborane moiety enhances the inhibitory potential against hABCG2.
  • This hybrid molecule offers a potential strategy to overcome BCRP-mediated multidrug resistance in cancer therapy.
Keywords:
ABCG2breast cancer resistance proteincarboranedrug resistancequinazoline

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