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Discovery of an Aldo-Keto reductase 1C3 (AKR1C3) degrader

Angelica V Carmona1, Shirisha Jonnalagadda1, Alfie M Case1

  • 1Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA.

Communications Chemistry
|April 29, 2024
PubMed

Insights

Researchers developed a novel PROTAC degrader targeting Aldo-keto reductase 1C3 (AKR1C3), a protein linked to cancer proliferation. This new compound effectively reduced AKR1C3 and androgen receptor splice variant 7 (ARv7) in prostate cancer cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Aldo-keto reductase 1C3 (AKR1C3) is upregulated in various cancers, including prostate cancer, contributing to tumor growth and treatment resistance.
  • Androgen receptor splice variant 7 (ARv7) is a key driver of resistance to androgen receptor signaling inhibitors in castration-resistant prostate cancer.
  • AKR1C3 stabilizes ARv7, exacerbating treatment resistance in prostate cancer.

Purpose of the Study:

  • To discover and characterize the first-in-class Proteolysis-Targeting Chimera (PROTAC) degrader for AKR1C3.
  • To evaluate the compound's efficacy in degrading AKR1C3 and its downstream effects in prostate cancer models.

Main Methods:

  • Development of a novel PROTAC molecule designed to induce degradation of AKR1C3.
  • Treatment of 22Rv1 prostate cancer cells with the AKR1C3 PROTAC degrader.
  • Quantification of AKR1C3, ARv7, and related isoforms (AKR1C1, AKR1C2) protein levels using degradation assays.

Main Results:

  • The first-generation AKR1C3 PROTAC degrader potently reduced AKR1C3 expression in 22Rv1 cells (DC50 = 52 nM).
  • Concomitant degradation of ARv7 was observed with a DC50 of 70 nM.
  • The compound also showed degradation of AKR1C1 and AKR1C2 isoforms to a lesser extent.

Conclusions:

  • The developed PROTAC molecule is the first-in-class degrader targeting AKR1C3.
  • This compound serves as a valuable chemical tool for studying AKR1C3 function in cancer.
  • The findings present a promising therapeutic strategy for prostate cancer intervention by targeting AKR1C3 and ARv7.

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