Erlotinib
From Proteopedia
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| - | <StructureSection load='' size=' | + | <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=== | ||
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* 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 [[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=== | ===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> | [[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> | ||
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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
Proteopedia Page Contributors and Editors (what is this?)
David Canner, Michal Harel, Joel L. Sussman, Alexander Berchansky
