Aldo-Keto Reductase 1C3 Inhibitor Prodrug Improves Pharmacokinetic Profile and Demonstrates In Vivo Efficacy in a Prostate Cancer Xenograft Model

Aldo-keto
reductase 1C3 (AKR1C3) is overexpressed in castration-resistant
prostate cancer where it acts to drive proliferation and aggressiveness
by producing androgens. The reductive action of the enzyme leads to
chemoresistance development against various clinical antineoplastics
across a range of cancers. Herein, we report the continued optimization
of selective AKR1C3 inhibitors and the identification of 5r, a potent AKR1C3 inhibitor (IC50 = 51 nM) with >1216-fold
selectivity for AKR1C3 over closely related isoforms. Due to the cognizance
of the poor pharmacokinetics associated with free carboxylic acids,
a methyl ester prodrug strategy was pursued. The prodrug 4r was converted to free acid 5r in vitro in mouse plasma
and in vivo. The in vivo pharmacokinetic evaluation revealed an increase
in systemic exposure and increased the maximum 5r concentration
compared to direct administration of the free acid. The prodrug 4r demonstrated a dose-dependent effect to reduce the tumor
volume of 22Rv1 prostate cancer xenografts without observed toxicity.