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Updated: Jul 24, 2025

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Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug

Siyu He1,2, Xianglin Chu1, Yujia Wu3

  • 1School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.

Journal of Medicinal Chemistry
|July 6, 2023
PubMed

Insights

Inhibiting the enzyme Aldo-keto reductase 1C3 (AKR1C3) can restore chemotherapy sensitivity in resistant cancers. A new inhibitor, S07-1066, synergized doxorubicin

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Aldo-keto reductase 1C3 (AKR1C3) is implicated in cancer development and resistance to chemotherapy.
  • AKR1C3 activity contributes to anthracycline (ANT) resistance in cancer cells.
  • Targeting AKR1C3 offers a strategy to re-sensitize cancers to chemotherapy.

Purpose of the Study:

  • To develop novel biaryl-containing inhibitors of AKR1C3.
  • To evaluate the efficacy of a lead inhibitor, S07-1066, in overcoming anthracycline resistance.

Main Methods:

  • Synthesis of a series of biaryl compounds targeting AKR1C3.
  • Assessment of inhibitor activity in cancer cell models (MCF-7) with varying AKR1C3 expression.
  • Evaluation of drug synergy and chemosensitization *in vitro* and *in vivo*.

Main Results:

  • The inhibitor S07-1066 selectively inhibited AKR1C3-mediated reduction of doxorubicin (DOX).
  • Co-treatment with S07-1066 synergized DOX cytotoxicity and reversed DOX resistance in AKR1C3-overexpressing cells.
  • The synergistic effects were confirmed in both *in vitro* and *in vivo* studies.

Conclusions:

  • Inhibition of AKR1C3 enhances the therapeutic efficacy of anthracyclines.
  • AKR1C3 inhibitors like S07-1066 show potential as adjuvants to overcome chemotherapy resistance.
  • This approach may improve cancer treatment outcomes for patients with AKR1C3-mediated resistance.

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