BI 6727, A Polo-like Kinase Inhibitor with Improved Pharmacokinetic Profile and Broad Antitumor Activity

• Published in: Clinical cancer research Vol. 15; no. 9; pp. 3094 - 3102
• Main Authors: RUDOLPH, Dorothea, STEEGMAIER, Martin, HOFFMANN, Matthias, GRAUERT, Matthias, BAUM, Anke, QUANT, Jens, HASLINGER, Christian, GARIN-CHESA, Pilar, ADOLF, Gunther R
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2009
• Subjects: 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; Antineoplastic agent; Enzyme; Kinase; Transferases; Inhibitor; Pharmacokinetics; Biological activity; Profile

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...