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Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer

Satoshi Endo1, Hiroaki Oguri1, Jin Segawa1

  • 1Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.

Journal of Medicinal Chemistry
|August 28, 2020
PubMed

Insights

Researchers discovered novel inhibitors targeting Aldo-keto reductase 1C3 (AKR1C3), crucial for prostate cancer growth. These compounds effectively suppressed cancer cell proliferation and tumor growth, enhancing existing treatments for castration-resistant prostate cancer (CRPC).

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Oncology

Background:

  • Aldo-keto reductase (AKR) 1C3 is vital for androgen synthesis, driving prostate cancer progression.
  • AKR1C3 also supports androgen-independent growth in castration-resistant prostate cancer (CRPC).
  • Elevated AKR1C3 in CRPC tissues makes it a key therapeutic target.

Purpose of the Study:

  • To identify and characterize novel, potent, and selective AKR1C3 inhibitors.
  • To elucidate the structural basis of AKR1C3 inhibition.
  • To evaluate the therapeutic potential of these inhibitors in preclinical models of prostate cancer.

Main Methods:

  • Synthesis of novel AKR1C3 inhibitors and their derivatives.
  • Enzyme inhibition assays to determine IC50 values and selectivity.
  • Crystallographic studies to understand inhibitor-target interactions.
  • Cell proliferation assays using prostate cancer cell lines (22Rv1, PC3).
  • In vivo studies using a prostate tumor xenograft mouse model.
  • Combination studies with established anti-CRPC drugs (abiraterone, enzalutamide).

Main Results:

  • A novel potent AKR1C3 inhibitor, compound 2d, was identified with derivatives exhibiting IC50 values of 25-56 nM.
  • Inhibitors demonstrated >220-fold selectivity over other AKR isoforms (1C1, 1C2, 1C4).
  • Crystallographic data revealed structural factors contributing to inhibitory potency.
  • The inhibitors suppressed proliferation of prostate cancer cells via both androgen-dependent and -independent pathways.
  • Compounds 2j and 2l effectively prevented tumor growth in a xenograft mouse model.
  • Inhibitors significantly enhanced apoptosis induced by abiraterone or enzalutamide.

Conclusions:

  • Novel AKR1C3 inhibitors with high potency and selectivity were developed.
  • These inhibitors demonstrate efficacy in suppressing prostate cancer cell growth and tumor progression.
  • The findings support the therapeutic potential of AKR1C3 inhibitors, alone or in combination, for treating CRPC.

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