Preclinical analysis of the analinoquinazoline AG1478, a specific small molecule inhibitor of EGF receptor tyrosine kinase

Biochemical Pharmacology
A G EllisEdouard C Nice

Abstract

The tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) is a potent and specific inhibitor of EGFR tyrosine kinase whose favourable preclinical profile supports progression towards clinical trials. Microphysiometric evaluation revealed a short (<24 min) effective inhibition of cellular receptor response to EGF challenge in BaF/ERX cells indicating a need to maintain sustained levels of inhibitor. Initial pharmacokinetic evaluation in mice of novel AG1478 formulations in a beta-cyclodextrin (Captisol) showed monoexponential elimination from plasma (half-life 30 min) following subcutaneous administration. A two-fold dose escalation gave a 2.4-fold increase in the total AUC. Bolus i.v. and 6 h continuous infusion were investigated in rats to mimic a more clinically relevant administration regimen. Drug elimination following bolus i.v. administration was biphasic (terminal elimination half-life 30-48 min). The linear relationship between dose and AUC(0-->infinity) (r2=0.979) enabled the prediction of infusion rates and doses for sustained delivery using continuous 6 h infusions, where steady state was reached in 120 min. Plasma levels of AG1478>10 microM were achieved over the duration of the infusion. At the lowest do...Continue Reading

References

May 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·J C OwickiH M McConnell
Nov 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·N SugawaV P Collins
Mar 15, 1967·Annals of the New York Academy of Sciences·E R SmithM M Mason
Nov 1, 1994·European Journal of Biochemistry·N Osherov, A Levitzki
Mar 24, 1995·Science·A Levitzki, A Gazit
Oct 1, 1996·Journal of Pharmaceutical Sciences·T Loftsson, M E Brewster
Dec 23, 1998·Proceedings of the National Academy of Sciences of the United States of America·D A LauffenburgerH S Wiley
Dec 3, 1999·The British Journal of Dermatology·T J PowellA Levitzki
Mar 17, 2001·Nature Reviews. Molecular Cell Biology·Y Yarden, M X Sliwkowski
Jun 28, 2001·Oncogene·J Mendelsohn, J Baselga
Feb 28, 2002·Annals of Oncology : Official Journal of the European Society for Medical Oncology·J Baselga
Jun 28, 2002·Cancer Cell·Laura K ShawverAxel Ullrich
Jul 13, 2002·Journal of Cellular Physiology·Kevin E H LuiSuzanne M Bernier
Aug 23, 2002·Pharmacology & Therapeutics·William A Denny
Nov 8, 2002·British Medical Bulletin·Johann S de Bono, Eric K Rowinsky
Jan 8, 2003·Proceedings of the National Academy of Sciences of the United States of America·Achim A JungbluthWebster K Cavanee
May 16, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Masahiro FukuokaJosé Baselga
Jun 18, 2003·Accounts of Chemical Research·Alexander Levitzki
Oct 7, 2003·Molecular Cell·Antony W BurgessShigeyuki Yokoyama
Dec 17, 2003·Proceedings of the National Academy of Sciences of the United States of America·Terrance G JohnsAndrew M Scott
Mar 16, 2004·The Journal of Biological Chemistry·Francesca WalkerAntony W Burgess
Mar 23, 2004·Current Medicinal Chemistry. Anti-cancer Agents·M TiseoA Ardizzoni
Dec 2, 2004·Nature Reviews. Drug Discovery·Mark E Davis, Marcus E Brewster
Jan 11, 2005·Clinical Lung Cancer·L Minerva Burgos Fuster, Alan B Sandler
Feb 17, 2005·Journal of the National Cancer Institute·Renee Twombly
Mar 9, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·José Baselga, Carlos L Arteaga
Apr 14, 2005·Molecular Cancer Therapeutics·David McKillopTrevor C Stephens
Sep 8, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Rushika M PereraTerrance G Johns

❮ Previous
Next ❯

Citations

Jan 9, 2008·Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract·Christopher ChristophiTheodora Fifis
Mar 12, 2009·Journal of Molecular Neuroscience : MN·Avril PereiraSuresh Sundram
Mar 10, 2012·Reproduction, Fertility, and Development·Rebecca KleinIsabella Gashaw
Sep 29, 2012·Proceedings of the National Academy of Sciences of the United States of America·Jes K Klarlund
May 14, 2010·Molecular Biology of the Cell·Ethan R BlockJes K Klarlund
Jun 20, 2008·American Journal of Physiology. Cell Physiology·Tushar B DebMichael D Johnson
Dec 17, 2009·World Journal of Gastroenterology : WJG·Bruno-Christian KoehlerHenning Schulze-Bergkamen
Dec 18, 2012·Reproduction : the Official Journal of the Society for the Study of Fertility·Shun ZhangWei Li
Nov 13, 2012·Progress in Neuro-psychopharmacology & Biological Psychiatry·Avril PereiraSuresh Sundram
Mar 27, 2015·Neoplasia : an International Journal for Oncology Research·Hongxiang WangJuxiang Chen
Mar 29, 2011·Experimental Cell Research·Estefanía Carrasco-GarcíaIsabel Martínez-Lacaci
Apr 21, 2009·European Journal of Pharmacology·Gérémy Abdull KoumbadingaFrançois Marceau
Feb 10, 2012·The Journal of Investigative Dermatology·Frank LiebelMichael D Southall
Dec 9, 2008·Biochemical Pharmacology·Zhi ShiZhe-Sheng Chen
Mar 4, 2008·Toxicology and Applied Pharmacology·Cordelia J BarrickDavid W Threadgill
Dec 21, 2010·The Journal of Pathology·Asem ShalabyAdrienne M Flanagan
Jul 10, 2009·International Journal of Cancer. Journal International Du Cancer·M KeeseP Bastiaens
Aug 9, 2008·The American Journal of Pathology·Silvia GoldoniRenato V Iozzo
Aug 27, 2010·Biology of Reproduction·J K WrightS J Lye
Jan 29, 2014·Antimicrobial Agents and Chemotherapy·Ranjan BeheraKojo Mensa-Wilmot
Mar 20, 2019·Journal of Molecular Neuroscience : MN·Marienela Buendia DuqueRafael Roesler
Oct 11, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Greta GarridoLuis Enrique Fernández
Apr 28, 2017·Proceedings of the National Academy of Sciences of the United States of America·Jeffrey M HarderSimon W M John
Aug 31, 2020·Molecular Biology Reports·Kelly V PinheiroRafael Roesler
Jun 24, 2009·Chemical Reviews·Mats Ljungman
Jun 7, 2014·Chemical Reviews·Qingjun LiuPing Wang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Bioinformatics in Biomedicine

Bioinformatics in biomedicine incorporates computer science, biology, chemistry, medicine, mathematics and statistics. Discover the latest research on bioinformatics in biomedicine here.

Cell Signaling by Tyrosine Kinases

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. RTKs have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Discover the latest research on cell signaling and RTK here.

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.