Erlotinib: Difference between revisions
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< | <StructureSection load='' size='450' side='right' scene='Erlotinib/Erlotinib/1' caption='Erlotinib, also known as Tarceva'> | ||
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===Better Known as: Tarceva=== | ===Better Known as: Tarceva=== | ||
* Marketed By: Genentech, OSI Pharmaceutials, & Roche | * Marketed By: Genentech, OSI Pharmaceutials, & Roche | ||
* Major Indication: Pancreatic & Small | * Major Indication: Pancreatic & Small Cell Lung [[Cancer]] | ||
* Drug Class: [[EGFR]] Inhibitor | * Drug Class: [[EGFR]] Inhibitor | ||
* Date of FDA Approval (Expiration): 2005 (2020) | * Date of FDA Approval (Expiration): 2005 (2020) | ||
* 2009 Sales: $1.2 Billion | * 2009 Sales: $1.2 Billion | ||
* Importance: It is one of the best selling and most effective treatments for several types of cancer. It is an improved version of [[Iressa]]. | * Importance: It is one of the best selling and most effective treatments for several types of cancer. It is an improved version of [[Iressa]]. | ||
* | * See [[Pharmaceutical Drugs]] for more information about other drugs and disorders | ||
* See also [[Journal:JBSD:26|Investigation on the Site-Selective Binding of Bovine Serum Albumin by Erlotinib Hydrochloride]] | |||
===Mechanism of Action=== | |||
[[EGFR|Epidermal Growth Factor Receptors]] are overexpressed in many types of human [[Cancer|carcinomas]] including lung, pancreatic, and breast cancer, and are often mutated. This overexpression leads to excessive activation of the anti-apoptotic [[Ras]] signalling cascade, resulting in uncontrolled [[DNA_Replication|DNA synthesis]] and cell proliferation. Studies have revealed that the <scene name='Erlotinib/Kinase/1'>EGFR tyrosine kinase domain</scene> is responsible for activating this Ras signaling cascade. Upon binding ligands like Epidermal Growth Factor, EGFR dimerizes and autophosphorylates several tyrosine residues at its C-terminal domain. Upon phosphorylation, EGFR undergoes a conformational change, revealing an additional binding site capable of eliciting downstream activation of other signaling proteins.<ref>PMID:6090945</ref><ref>PMID:16729045</ref> Erlotinib inhibits the EGFR tyrosine kinase by <scene name='Erlotinib/Bound/1'>binding to the ATP-binding site</scene> located within the kinase domain. EGFR uses residues Asp 831, Lys 721, Thr 766, Leu 820, Gly 772, Phe 771, Leu 694, Pro 770, Met 769, Leu 768, Gln 767 & Ala 719 to tightly bind the inhibitor. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.<ref>PMID:15284455</ref><ref>PMID:11129168</ref> | |||
===Pharmacokinetics=== | ===Pharmacokinetics=== | ||
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{{:Tyrosine Kinase Inhibitor Pharmacokinetics}} | |||
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===References=== | ===References=== | ||
<references/> | <references/> | ||
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Latest revision as of 17:39, 17 November 2019
Better Known as: Tarceva
Mechanism of ActionEpidermal Growth Factor Receptors are overexpressed in many types of human carcinomas including lung, pancreatic, and breast cancer, and are often mutated. This overexpression leads to excessive activation of the anti-apoptotic Ras signalling cascade, resulting in uncontrolled DNA synthesis and cell proliferation. Studies have revealed that the is responsible for activating this Ras signaling cascade. Upon binding ligands like Epidermal Growth Factor, EGFR dimerizes and autophosphorylates several tyrosine residues at its C-terminal domain. Upon phosphorylation, EGFR undergoes a conformational change, revealing an additional binding site capable of eliciting downstream activation of other signaling proteins.[1][2] Erlotinib inhibits the EGFR tyrosine kinase by located within the kinase domain. EGFR uses residues Asp 831, Lys 721, Thr 766, Leu 820, Gly 772, Phe 771, Leu 694, Pro 770, Met 769, Leu 768, Gln 767 & Ala 719 to tightly bind the inhibitor. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.[3][4] Pharmacokinetics
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References
- ↑ Downward J, Parker P, Waterfield MD. Autophosphorylation sites on the epidermal growth factor receptor. Nature. 1984 Oct 4-10;311(5985):483-5. PMID:6090945
- ↑ Oda K, Matsuoka Y, Funahashi A, Kitano H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol. 2005;1:2005.0010. Epub 2005 May 25. PMID:16729045 doi:10.1038/msb4100014
- ↑ Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004 Aug 20;305(5687):1163-7. Epub 2004 Jul 29. PMID:15284455 doi:10.1126/science.1101637
- ↑ Raymond E, Faivre S, Armand JP. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs. 2000;60 Suppl 1:15-23; discussion 41-2. PMID:11129168