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01-02-2013 | Original Article

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

Authors: Jianxia Guo, Dana M. Clausen, Jan H. Beumer, Robert A. Parise, Merrill J. Egorin, Karla Bravo-Altamirano, Peter Wipf, Elizabeth R. Sharlow, Qiming Jane Wang, Julie L. Eiseman

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2013

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.

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Title: 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
Authors: Jianxia Guo
Dana M. Clausen
Jan H. Beumer
Robert A. Parise
Merrill J. Egorin
Karla Bravo-Altamirano
Peter Wipf
Elizabeth R. Sharlow
Qiming Jane Wang
Julie L. Eiseman
Publication date: 01-02-2013
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2013
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-012-2010-z

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