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Polymethoxylated N-Carboranyl Isoquinolinones: A New Scaffold for ABCG2 Inhibitors
Lydia Kuhnert1, Philipp Stockmann2, Peter Lönnecke2
1Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Universität Leipzig, Leipzig, Germany.
Chemmedchem
|February 12, 2026
Summary
New carborane-containing isoquinolinones effectively inhibit ABCG2, overcoming multidrug resistance (MDR) in cancer. These compounds show promise as adjuvant therapeutics, resensitizing cancer cells to chemotherapy drugs like mitoxantrone.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Drug Discovery
Background:
- Multidrug resistance (MDR) mediated by ABCG2 transporter is a significant obstacle in cancer chemotherapy.
- Development of potent and non-toxic ABCG2 inhibitors is crucial for effective cancer treatment.
Purpose of the Study:
- To design, synthesize, and evaluate novel carborane-containing isoquinolinone derivatives as ABCG2 inhibitors.
- To assess the potential of these compounds to overcome ABCG2-mediated multidrug resistance in cancer.
Main Methods:
- Computational docking analyses guided the design of isoquinolinone frameworks.
- Synthesis of novel carborane-containing N-carboranyl isoquinolinones.
- Evaluation of cytotoxicity, ABCG2 inhibition, and reversal of mitoxantrone resistance in an ABCG2-expressing cell model.
Main Results:
- Several synthesized isoquinolinone derivatives, particularly those with methoxyphenyl substitutions, demonstrated potent ABCG2 inhibition.
- Compounds IC-1 to IC-6 exhibited favorable solubility and lower toxicity compared to IC-7 to IC-11.
- Specific derivatives (IC-10, IC-11) significantly reversed mitoxantrone resistance, indicating effective resensitization of cancer cells.
Conclusions:
- Carborane-containing isoquinolinones with methoxy groups are promising candidates for novel ABCG2 inhibitors.
- These compounds offer a potential strategy to overcome ABCG2-mediated multidrug resistance in various cancers.
- Further development could lead to improved adjuvant therapeutics for cancer chemotherapy.
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