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

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

  • J Med Chem. 2023 Jul 27;66(14):9894-9915. doi: 10.1021/acs.jmedchem.3c00732.
Krishnaiah Maddeboina 1,  Sravan K Jonnalagadda 1,  Ahmed Morsy 1,  Ling Duan 2,  Yashpal S Chhonker 3,  Daryl J Murry 3 4,  Trevor M Penning 2,  Paul C Trippier 1 4 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68106, United States.
  • 2 Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 3 Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68106, United States.
  • 4 Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68106, United States.
  • 5 UNMC Center for Drug Discovery, University of Nebraska Medical Center, Omaha, Nebraska 68106, United States.
PMID: 37428858 DOI: 10.1021/acs.jmedchem.3c00732
Abstract

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.

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