Original Article

Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 2, pp 331-344

In vitro cytotoxicity, pharmacokinetics, tissue distribution, and metabolism of small-molecule protein kinase D inhibitors, kb-NB142-70 and kb-NB165-09, in mice bearing human cancer xenografts

  • Jianxia GuoAffiliated withMolecular Therapeutics and Drug Discovery, The University of Pittsburgh Cancer Institute, Hillman Cancer CenterDepartment of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh
  • , Dana M. ClausenAffiliated withMolecular Therapeutics and Drug Discovery, The University of Pittsburgh Cancer Institute, Hillman Cancer Center
  • , Jan H. BeumerAffiliated withMolecular Therapeutics and Drug Discovery, The University of Pittsburgh Cancer Institute, Hillman Cancer CenterDepartment of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh
  • , Robert A. PariseAffiliated withMolecular Therapeutics and Drug Discovery, The University of Pittsburgh Cancer Institute, Hillman Cancer CenterDepartment of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh
  • , Merrill J. EgorinAffiliated withMolecular Therapeutics and Drug Discovery, The University of Pittsburgh Cancer Institute, Hillman Cancer CenterDepartment of Pharmacology and Chemical Biology, School of Medicine, University of PittsburghDepartment of Medicine, School of Medicine, University of Pittsburgh
  • , Karla Bravo-AltamiranoAffiliated withDepartment of Chemistry, University of Pittsburgh
  • , Peter WipfAffiliated withMolecular Therapeutics and Drug Discovery, The University of Pittsburgh Cancer Institute, Hillman Cancer CenterDepartment of Chemistry, University of Pittsburgh
  • , Elizabeth R. SharlowAffiliated withDepartment of Pharmacology, University of Virginia
  • , Qiming Jane WangAffiliated withDepartment of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh
    • , Julie L. EisemanAffiliated withMolecular Therapeutics and Drug Discovery, The University of Pittsburgh Cancer Institute, Hillman Cancer CenterDepartment of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh Email author 

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Abstract

Purpose

Protein kinase D (PKD) mediates diverse biological responses including cell growth and survival. Therefore, PKD inhibitors may have therapeutic potential. We evaluated the in vitro cytotoxicity of two PKD inhibitors, kb-NB142-70 and its methoxy analogue, kb-NB165-09, and examined their in vivo efficacy and pharmacokinetics.

Methods

The in vitro cytotoxicities of kb-NB142-70 and kb-NB165-09 were evaluated by MTT assay against PC-3, androgen-independent prostate cancer cells, and CFPAC-1 and PANC-1, pancreatic cancer cells. Efficacy studies were conducted in mice bearing either PC-3 or CPFAC-1 xenografts. Tumor-bearing mice were euthanized between 5 and 1,440 min after iv dosing, and plasma and tissue concentrations were measured by HPLC–UV. Metabolites were characterized by LC–MS/MS.

Results

kb-NB142-70 and kb-NB165-09 inhibited cellular growth in the low–mid μM range. The compounds were inactive when administered to tumor-bearing mice. In mice treated with kb-NB142-70, the plasma C max was 36.9 nmol/mL, and the PC-3 tumor C max was 11.8 nmol/g. In mice dosed with kb-NB165-09, the plasma C max was 61.9 nmol/mL, while the PANC-1 tumor C max was 8.0 nmol/g. The plasma half-lives of kb-NB142-70 and kb-NB165-09 were 6 and 14 min, respectively. Both compounds underwent oxidation and glucuronidation.

Conclusions

kb-NB142-70 and kb-NB165-09 were rapidly metabolized, and concentrations in tumor were lower than those required for in vitro cytotoxicity. Replacement of the phenolic hydroxyl group with a methoxy group increased the plasma half-life of kb-NB165-09 2.3-fold over that of kb-NB142-70. Rapid metabolism in mice suggests that next-generation compounds will require further structural modifications to increase potency and/or metabolic stability.

Keywords

Protein kinase D (PKD) inhibitors Pharmacokinetics Prostate cancer Pancreatic cancer kb-NB142-70 kb-NB165-09