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

摘要: 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 inhibitors, kb-NB142-70 its methoxy analogue, kb-NB165-09, examined their vivo efficacy pharmacokinetics. The cytotoxicities kb-NB165-09 were by MTT assay against PC-3, androgen-independent prostate cancer cells, CFPAC-1 PANC-1, pancreatic cells. Efficacy studies conducted mice bearing either PC-3 or CPFAC-1 xenografts. Tumor-bearing euthanized between 5 1,440 min after iv dosing, plasma tissue concentrations measured HPLC–UV. Metabolites characterized LC–MS/MS. inhibited cellular low–mid μM range. compounds inactive when administered to tumor-bearing mice. In treated with kb-NB142-70, C max was 36.9 nmol/mL, tumor 11.8 nmol/g. dosed 61.9 nmol/mL, while PANC-1 8.0 nmol/g. half-lives 6 14 min, respectively. Both underwent oxidation glucuronidation. rapidly metabolized, lower than those required for cytotoxicity. Replacement phenolic hydroxyl group a increased half-life 2.3-fold over that kb-NB142-70. Rapid metabolism suggests next-generation will require further structural modifications increase potency and/or metabolic stability.