| Abstract: |
N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 {N-[5-[[[5-(1,1-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032}, has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC50 = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC50 = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a sc/ ip A2780 human ovarian carcinoma xenograft model. |
| Keywords: |
controlled study; unclassified drug; human cell; area under the curve; drug efficacy; nonhuman; antineoplastic agents; antineoplastic agent; animal cell; mouse; animals; mice; animal experiment; animal model; antineoplastic activity; drug structure; tumor xenograft; drug screening assays, antitumor; cell line, tumor; structure activity relation; structure-activity relationship; phosphorylation; dog; dogs; rat; ovary carcinoma; transplantation, heterologous; drug clearance; models, molecular; crystallography, x-ray; molecular structure; tumor model; rats; flavopiridol; drug bioavailability; drug metabolism; maximum tolerated dose; neoplasm transplantation; cell free system; cyclin dependent kinase inhibitor; n [5 (5 tert butyl 2 oxazolylmethylthio) 2 thiazolyl]isonipecotamide; thiazoles; retinoblastoma protein; drug protein binding; drug stability; cyclin e; cyclin dependent kinase 4; cyclin dependent kinase 1; cell mediated cytotoxicity; microsomes, liver; cyclin dependent kinase 2; cyclin-dependent kinase 2; plasma half life; cell-free system; oxazoles; cdc2-cdc28 kinases; humans; human; article; aminothiazole; n [5 [[[5 (1,1 dimethylethyl) 2 oxazolyl]methyl]thio] 2 thiazolyl] 4 piperidinecarboxamide
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