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Cancer Chemother Pharmacol. 2013 Feb;71(2):331-44. doi: 10.1007/s00280-012-2010-z. Epub 2012 Oct 30.

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.

Author information

1
Molecular Therapeutics and Drug Discovery, The University of Pittsburgh Cancer Institute, Hillman Cancer Center, 5117 Centre Ave, Room G27b, Pittsburgh, PA 15213, USA.

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.

PMID:
23108699
PMCID:
PMC3557573
DOI:
10.1007/s00280-012-2010-z
[Indexed for MEDLINE]
Free PMC Article

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