Clinical cancer research, 2009-05, Vol.15 (9), p.3094-3102
2009
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- Autor(en) / Beteiligte
- Titel
- BI 6727, A Polo-like Kinase Inhibitor with Improved Pharmacokinetic Profile and Broad Antitumor Activity
- Ist Teil von
- Clinical cancer research, 2009-05, Vol.15 (9), p.3094-3102
- Ort / Verlag
- Philadelphia, PA: American Association for Cancer Research
- Erscheinungsjahr
- 2009
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Purpose: Antimitotic chemotherapy remains a cornerstone of multimodality treatment for locally advanced and metastatic cancers. To identify novel mitosis-specific agents with higher selectivity than approved tubulin-binding agents (taxanes, Vinca alkaloids), we have generated inhibitors of Polo-like kinase 1, a target that functions predominantly in mitosis. Experimental Design: The first compound in this series, suitable for i.v. administration, has entered clinical development. To fully explore the potential of Polo-like kinase 1 inhibition in oncology, we have profiled additional compounds and now describe a novel clinical candidate. Results: BI 6727 is a highly potent (enzyme IC 50 = 0.87 nmol/L, EC 50 = 11-37 nmol/L on a panel of cancer cell lines) and selective dihydropteridinone with distinct properties. First, BI 6727 has a pharmacokinetic profile favoring sustained exposure of tumor tissues with a high volume of distribution and a long terminal half-life in mice ( V ss = 7.6 L/kg, t 1/2 = 46 h) and rats ( V ss = 22 L/kg, t 1/2 = 54 h). Second, BI 6727 has physicochemical and pharmacokinetic properties that allow in vivo testing of i.v. as well as oral formulations, adding flexibility to dosing schedules. Finally, BI 6727 shows marked antitumor activity in multiple cancer models, including a model of taxane-resistant colorectal cancer. With oral and i.v. routes of administration, the total weekly dose of BI 6727 is most relevant for efficacy, supporting the use of a variety of well-tolerated dosing schedules. Conclusion: These findings warrant further investigation of BI 6727 as a tailored antimitotic agent; clinical studies have been initiated.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1078-0432eISSN: 1557-3265DOI: 10.1158/1078-0432.CCR-08-2445Titel-ID: cdi_crossref_primary_10_1158_1078_0432_CCR_08_2445
- Format
- –
- Schlagworte
- Animals, Antineoplastic agents, Antineoplastic Agents - chemistry, Antineoplastic Agents - pharmacokinetics, Antineoplastic Agents - pharmacology, Apoptosis - drug effects, BI 6727, Biological and medical sciences, Blotting, Western, Carcinoma, Non-Small-Cell Lung - drug therapy, Carcinoma, Non-Small-Cell Lung - enzymology, Carcinoma, Non-Small-Cell Lung - pathology, Cell Cycle - drug effects, Cell Cycle Proteins - antagonists & inhibitors, Cell Cycle Proteins - metabolism, Cell Line, Tumor, Cell Proliferation - drug effects, Colonic Neoplasms - drug therapy, Colonic Neoplasms - enzymology, Colonic Neoplasms - pathology, Crystallography, X-Ray, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacokinetics, Enzyme Inhibitors - pharmacology, Female, Fluorescent Antibody Technique, Forkhead Transcription Factors - physiology, Humans, Immunoenzyme Techniques, Lung Neoplasms - drug therapy, Lung Neoplasms - enzymology, Lung Neoplasms - pathology, Medical sciences, Mice, Mice, Nude, monopolar spindle, Pharmacology. Drug treatments, Plk, Polo-arrest, Polo-Like Kinase 1, Polo-like kinase inhibitor, Protein Conformation, Protein Serine-Threonine Kinases - antagonists & inhibitors, Protein Serine-Threonine Kinases - metabolism, Proto-Oncogene Proteins - antagonists & inhibitors, Proto-Oncogene Proteins - metabolism, Pteridines - chemistry, Pteridines - pharmacokinetics, Pteridines - pharmacology, Rats, Rats, Wistar, Tissue Distribution, Xenograft Model Antitumor Assays