erlotinib   Click here for help

GtoPdb Ligand ID: 4920

Synonyms: NSC 718781 | OSI 744 | OSI-774 | R 1415 | Tarceva®
Approved drug PDB Ligand
erlotinib is an approved drug (FDA (2004), EMA (2005))
Compound class: Synthetic organic
Comment: Erlotinib is a clinically approved type-1 inhibitor of the epidermal growth factor receptor (EGFR) receptor tyrosine kinase. This drug shows some selectivity for EGFR exon 19 deletion or exon 21 L858R mutations over the wild type receptor.
Subsequent studies have shown erlotinib to be a potent inhibitor of JAK2V617F activity. JAK2V617F, a mutant from of tyrosine kinase JAK2, is found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. Study suggests that erlotinib may be used for treatment of JAK2V617F-positive PV and other myeloproliferative disorders. Specificity of inhibition with regard to other tyrosine kinase receptors remains to be fully characterized. Erlotinib is a Type-1 kinase inhibitor.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 5
Hydrogen bond donors 1
Rotatable bonds 10
Topological polar surface area 74.73
Molecular weight 393.17
XLogP 2.7
No. Lipinski's rules broken 0
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Canonical SMILES COCCOc1cc2c(ncnc2cc1OCCOC)Nc1cccc(c1)C#C
Isomeric SMILES COCCOc1cc2c(ncnc2cc1OCCOC)Nc1cccc(c1)C#C
InChI InChI=1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
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Summary of Clinical Use Click here for help
Erlotinib is used to treat advanced or metastatic non-small lung cancer, pancreatic cancer, and other cancers. The clinically administered form is the hydrochloride salt (PubChem CID 176871). As of October 2016, the US FDA has limited treatment with erlotinib to patients with EGFR mutation-positive non-small cell lung cancer (NSCLC).
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase by binding, in a potent yet reversible fashion, to the adenosine triphosphate (ATP) binding site of the receptor and subsequently inhibits the intracellular phosphorylation of EGFR, resulting in cell stasis and/or death. Erlotinib binding affinity for EGFR exon 19 deletion or exon 21 L858R mutations is higher than its affinity for the wild type receptor.
Pharmacokinetics Click here for help
Erlotinib oral dose reaches peak plasma concentration within 4h, with a bioavailability of 60%. Bioavailability is increased to 100% when administered with food. 90% circulates bound to serum albumim and α1-acid glycoproteins.
Median half-life is 36.2 hours. Erlotinib is primarily metabolized by CYP3A4 and, to a lesser degree, by CYP1A2 and the extrahepatic isoforms CYP3A4 (intestine), CYP1A1 (lung) and CYP1B1 (tumor tissue).
Eliminated predominantly as metabolites in the feces (>90%) with a small amount eliminated in urine (< 9 %) of an oral dose. Less than 2% of the orally administered dose is excreted in an un-metabilized form.
Population pharmacokinetics
No clinically significant relationship between predicted apparent clearance and patient age, bodyweight, gender or ethnicity have been reported. Current smokers should be advised to stop smoking while taking erlotinib as smokers show an increased rate of drug clearance compared to non-smokers.
Organ function impairment
Although erlotinib exposure is similar in patients with moderately impaired hepatic function compared with patients with normal hepatic function (including patients with primary liver cancer or hepatic metastases) this drug should be used with caution in patients with liver function impairment as clinical study shows that the risk of hepatic toxicity is increased in patients with baseline hepatic impairment. Pharmacokinetics of erlotinib in patients with compromised renal function have not been studied.
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