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Discovery of Highly Selective AKR1C3 Inhibitors to Overcome EGFR C797S-Mediated Osimertinib Resistance in Non-Small

Can Guo1, Xiaolong Wang1, Qianwen Guan1

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

Journal of Medicinal Chemistry
|January 30, 2026
PubMed

Insights

A novel strategy targets aldo-keto reductase 1C3 (AKR1C3) to overcome osimertinib resistance in non-small cell lung cancer (NSCLC) with EGFR C797S mutations. The inhibitor SG-55 synergizes with osimertinib, showing promise for resistant lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Osimertinib resistance in non-small cell lung cancer (NSCLC) driven by EGFR C797S mutations is a significant clinical challenge.
  • Aldo-keto reductase 1C3 (AKR1C3) is identified as a key metabolic vulnerability sustaining glutathione-reactive oxygen species (GSH-ROS) homeostasis in resistant NSCLC cells.

Purpose of the Study:

  • To develop a novel therapeutic strategy targeting AKR1C3 to overcome osimertinib resistance mediated by the EGFR C797S mutation in NSCLC.
  • To identify and optimize potent and selective AKR1C3 inhibitors for combination therapy with osimertinib.

Main Methods:

  • Structure-guided optimization of a selective AKR1C3 inhibitor (S07-2001) to generate advanced analogues, culminating in SG-55.
  • Biochemical and cellular assays to evaluate the potency and selectivity of SG-55 against AKR1C3 and related enzymes.
  • Assessment of SG-55's effects on cellular redox homeostasis (NADPH/NADP+, GSH/GSSG ratios) and DNA damage in resistant NSCLC cells.
  • Combination studies with osimertinib to evaluate synergistic effects on proliferation, clonogenicity, and survival in vitro and in vivo.

Main Results:

  • SG-55 emerged as a potent, noncompetitive AKR1C3 inhibitor with nanomolar potency (IC50 = 5 ± 1 nM) and high selectivity (>10 μM against AKR1C1, AKR1C2, AKR1C4).
  • In EGFR C797S-mutant NSCLC cells, SG-55 modulated redox balance, induced DNA double-strand breaks, and synergized with osimertinib to significantly suppress cancer cell growth and survival.
  • The combination therapy demonstrated efficacy in preclinical xenograft models and exhibited favorable pharmacokinetics in mice.

Conclusions:

  • AKR1C3 blockade represents a viable "metabolism-targeted" strategy to overcome osimertinib resistance in NSCLC harboring the EGFR C797S mutation.
  • The potent AKR1C3 inhibitor SG-55, in combination with osimertinib, shows significant therapeutic potential for treating resistant NSCLC.
  • Targeting metabolic vulnerabilities offers a promising avenue for developing next-generation cancer therapies.

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