ArticleCancer chemotherapy and pharmacology2013
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.
Article in Cancer chemotherapy and pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Protein kinase D1 - A targetable mediator of pancreatic cancer development.Biochimica et biophysica acta. Molecular cell research · 2024Review
- Protein Kinase D2 and D3 Promote Prostate Cancer Cell Bone Metastasis by Positively Regulating Runx2 in a MEK/ERK1/2-Dependent Manner.The American journal of pathology · 2023Article
- Potential role for protein kinase D inhibitors in prostate cancer.Journal of molecular medicine (Berlin, Germany) · 2023Review
- Small Molecule Inhibitors of Protein Kinase D: Early Development, Current Approaches, and Future Directions.Journal of medicinal chemistry · 2023Review
- Small-Molecule Inhibitor Targeting Protein Kinase D: A Potential Therapeutic Strategy.Frontiers in oncology · 2021Review
- Protein kinase Ds promote tumor angiogenesis through mast cell recruitment and expression of angiogenic factors in prostate cancer microenvironment.Journal of experimental & clinical cancer research : CR · 2019Article
- Protein kinase D signaling in cancer: A friend or foe?Biochimica et biophysica acta. Reviews on cancer · 2017Review
- Antigliadin Antibodies (AGA IgG) Are Related to Neurochemistry in Schizophrenia.Frontiers in psychiatry · 2017Article
- Protein Kinase D: A Potential Therapeutic Target in Prostate Cancer.Molecular and cellular pharmacology · 2017Article
- Protein kinase D enzymes: novel kinase targets in pancreatic cancer.Expert review of gastroenterology & hepatology · 2015Review
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- Protein kinase d as a potential chemotherapeutic target for colorectal cancer.Molecular cancer therapeutics · 2014Article
- New pyrazolopyrimidine inhibitors of protein kinase d as potent anticancer agents for prostate cancer cells.PloS one · 2013Article
- Synthesis and Structure-Activity Relationships of Benzothienothiazepinone Inhibitors of Protein Kinase D.ACS medicinal chemistry letters · 2011Article
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Authors and funding
10 authors.
Funding
Abstract
purposeProtein 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.
methodsThe 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.
resultskb-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.
conclusionskb-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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