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Identification of a novel chalcone derivative as ferroptosis inducer through targeting TrxR in prostate cancer

Jun Yan1, Long Cheng2, Qing-Qing Ma2

  • 1The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510720, China; Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.

Biochemical Pharmacology
|January 29, 2026
PubMed

Insights

A novel chalcone derivative, CD-15, effectively inhibits prostate cancer (PCa) growth by targeting thioredoxin reductase (TrxR). This compound shows promise as a safe and effective therapy for castration-resistant prostate cancer (CRPC).

Area of Science:

  • Oncology
  • Drug Discovery
  • Biochemistry

Background:

  • Prostate cancer (PCa) progression to castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT) necessitates novel therapeutic strategies.
  • Current treatments often rely on the androgen receptor (AR) signaling pathway, which becomes ineffective in CRPC.

Purpose of the Study:

  • To identify and characterize novel therapeutic agents for PCa that are independent of the AR signaling pathway.
  • To investigate the anti-cancer mechanisms and therapeutic potential of compound CD-15.

Main Methods:

  • High-throughput screening of a compound library to identify anti-proliferative agents.
  • In vivo studies using cell line-derived xenograft (CDX) and zebrafish patient-derived xenograft (zPDX) models.
  • Drug affinity responsive target stability (DARTS) and virtual screening to identify the drug target.
  • Biochemical assays (BIAM, LC-MS/MS, molecular docking) to confirm target engagement and mechanism of action.

Main Results:

  • Compound CD-15, a chalcone derivative, demonstrated potent anti-proliferative activity against AR-negative PCa cells and inhibited tumor growth in vivo.
  • Thioredoxin reductase (TrxR) was identified as the direct target of CD-15, with TrxR over-expression observed in PCa patients.
  • CD-15 covalently binds to selenocysteine 498 in TrxR, inhibiting its activity and inducing ferroptosis, a TrxR-dependent anti-cancer mechanism.
  • CD-15 exhibited a more favorable safety profile compared to docetaxel.

Conclusions:

  • CD-15 is a promising therapeutic candidate for prostate cancer, particularly CRPC, due to its novel mechanism of action targeting TrxR.
  • The dual anti-PCa mechanism involving ferroptosis induction highlights CD-15's potential for overcoming treatment resistance.
  • Further investigation of CD-15 is warranted for its clinical development in prostate cancer treatment.
Keywords:
Chalcone derivativeDrug developmentFerroptosisProstate cancerThioredoxin reductase

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