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

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...

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Published inClinical 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
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LanguageEnglish
Published Philadelphia, PA American Association for Cancer Research 01.05.2009
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Abstract 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.
AbstractList 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 IC50 = 0.87 nmol/L, EC50 = 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 (Vss = 7.6 L/kg, t1/2 = 46 h) and rats (Vss = 22 L/kg, t1/2 = 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.
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. 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. 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. These findings warrant further investigation of BI 6727 as a tailored antimitotic agent; clinical studies have been initiated.
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.
Author Martin Steegmaier
Anke Baum
Günther R. Adolf
Dorothea Rudolph
Jens Quant
Pilar Garin-Chesa
Matthias Hoffmann
Matthias Grauert
Christian Haslinger
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  surname: RUDOLPH
  fullname: RUDOLPH, Dorothea
  organization: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
– sequence: 2
  givenname: Martin
  surname: STEEGMAIER
  fullname: STEEGMAIER, Martin
  organization: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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  givenname: Matthias
  surname: HOFFMANN
  fullname: HOFFMANN, Matthias
  organization: Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
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  givenname: Matthias
  surname: GRAUERT
  fullname: GRAUERT, Matthias
  organization: Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
– sequence: 5
  givenname: Anke
  surname: BAUM
  fullname: BAUM, Anke
  organization: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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  givenname: Jens
  surname: QUANT
  fullname: QUANT, Jens
  organization: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
– sequence: 7
  givenname: Christian
  surname: HASLINGER
  fullname: HASLINGER, Christian
  organization: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
– sequence: 8
  givenname: Pilar
  surname: GARIN-CHESA
  fullname: GARIN-CHESA, Pilar
  organization: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
– sequence: 9
  givenname: Gunther R
  surname: ADOLF
  fullname: ADOLF, Gunther R
  organization: Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
BackLink http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21723803$$DView record in Pascal Francis
https://www.ncbi.nlm.nih.gov/pubmed/19383823$$D View this record in MEDLINE/PubMed
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Pharmacokinetics
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Snippet Purpose: Antimitotic chemotherapy remains a cornerstone of multimodality treatment for locally advanced and metastatic cancers. To identify novel...
Antimitotic chemotherapy remains a cornerstone of multimodality treatment for locally advanced and metastatic cancers. To identify novel mitosis-specific...
Purpose: Antimitotic chemotherapy remains a cornerstone of multimodality treatment for locally advanced and metastatic cancers. To identify novel...
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StartPage 3094
SubjectTerms 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
Title BI 6727, A Polo-like Kinase Inhibitor with Improved Pharmacokinetic Profile and Broad Antitumor Activity
URI http://clincancerres.aacrjournals.org/content/15/9/3094.abstract
https://www.ncbi.nlm.nih.gov/pubmed/19383823
Volume 15
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