Erlotinib
Descripción general
Descripción
Erlotinib is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. It is primarily used in the treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer. This compound is marketed under the trade name Tarceva and has been a significant advancement in targeted cancer therapy .
Mecanismo De Acción
The mechanism of clinical antitumor action of erlotinib is not fully characterized. This compound inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells.
Although the exact mechanism of antineoplastic activity of this compound has not been fully elucidated, this compound appears to inhibit the intracellular phosphorylation of tyrosine kinase associated with EGFR, which is expressed on the surface of normal and cancer cells. Specificity with regard to other tyrosine kinase receptors has not been fully characterized.
This compound is a potent inhibitor of epidermal growth factor receptor tyrosine kinase and has been demonstrated to treat advanced or metastatic non-small cell lung cancer to prolong survival after failure of first-line or second-line chemotherapy. However, little is known about its effects on immune system. In the present study, /investigators/ aimed to investigate the immunosuppressive activity of this compound on T lymphocytes both in vitro and in vivo, and further explore its potential molecular mechanism. This compound exerted a significant inhibition on the T cell proliferation and activation induced by concanavalin A, anti-CD3 plus anti-CD28, staphylococcal enterotoxin B or phorbol myristate acetate respectively in a concentration-dependent manner and it also inhibited the secretion of the proinflammatory cytokines such as IL-2 and IFN-gamma of activated T cells. Further study showed that this compound caused G0/G1 arrest and suppressed the phosphorylations of c-Raf, ERK and Akt in activated T cells. Moreover, this compound significantly ameliorated picryl chloride-induced ear contact dermatitis in a dose-dependent manner in vivo. In summary, these findings suggest that this compound may cause the impairment of T-cell-mediated immune response both in vitro and in vivo through inhibiting T cell proliferation and activation, which is closely associated with its potent down-regulation of the c-Raf/ERK cascade and Akt signaling pathway.
Aplicaciones Científicas De Investigación
Erlotinib has a wide range of applications in scientific research:
Chemistry: Used as a model compound to study the inhibition of tyrosine kinases.
Biology: Investigated for its effects on cell signaling pathways and cancer cell proliferation.
Medicine: Extensively used in clinical trials and studies for the treatment of NSCLC and pancreatic cancer. It is also being explored for other cancers with EGFR mutations.
Industry: Employed in the development of new cancer therapies and as a reference compound in pharmaceutical research.
Análisis Bioquímico
Biochemical Properties
Erlotinib binds to the epidermal growth factor receptor (EGFR) tyrosine kinase in a reversible fashion at the adenosine triphosphate (ATP) binding site of the receptor . It has been found to be a potent inhibitor of JAK2V617F, a mutant form of tyrosine kinase JAK2 found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia .
Cellular Effects
This compound has significant antitumor activity in non-small cell lung cancer, pancreatic cancer, and several other types of cancer . It inhibits the intracellular phosphorylation of tyrosine kinase associated with the EGFR, thereby preventing further downstream signaling and resulting in cell death .
Molecular Mechanism
This compound exerts its effects at the molecular level by reversibly inhibiting the overall epidermal growth factor receptor (HER1/EGFR) - tyrosine kinase activity . This inhibition prevents intracellular phosphorylation, which in turn prevents further downstream signaling, resulting in cell death .
Temporal Effects in Laboratory Settings
This compound has shown a significant improvement in median survival, quality of life, and related symptoms in an unselected population of advanced and metastatic NSCLC patients in the second- or third-line setting . Furthermore, this compound has significant antitumor activity in first-line treatment .
Dosage Effects in Animal Models
In animal models, a minimally cytotoxic concentration of tunicamycin (1 μM) resulted in a significant increase in this compound-induced antiproliferative effects . This suggests that the effects of this compound can vary with different dosages in animal models .
Metabolic Pathways
Three major biotransformation pathways of this compound have been identified: O-demethylation of the side chains followed by oxidation to a carboxylic acid, M11 (29.4% of dose); oxidation of the acetylene moiety to a carboxylic acid, M6 (21.0%); and hydroxylation of the aromatic ring to M16 (9.6%) .
Transport and Distribution
This compound is predominantly distributed to the liver, which gradually moves to the intestine, thus highlighting hepatobiliary clearance . This compound also accumulates in the kidney cortex .
Subcellular Localization
This compound is retained in mitochondria/ER in tumor cells . This tumor cell-specific deposition of this compound, followed by light-triggered release of EGFR-inhibitory activity, may improve photodynamic therapy by attenuating tumor growth that is dependent on EGFR-derived signals .
Métodos De Preparación
Synthetic Routes and Reaction Conditions: Erlotinib is synthesized through a multi-step process involving the following key steps:
Formation of the Quinazoline Core: The synthesis begins with the formation of the quinazoline core, which is achieved by reacting 2,4-dichloroquinazoline with 3-ethynylaniline.
Substitution Reactions: The intermediate product undergoes substitution reactions with 2-methoxyethanol to introduce the methoxyethoxy groups at positions 6 and 7 of the quinazoline ring.
Final Coupling: The final step involves coupling the substituted quinazoline with 3-ethynylaniline under basic conditions to yield this compound.
Industrial Production Methods: Industrial production of this compound follows similar synthetic routes but is optimized for large-scale production. This involves the use of high-yield reactions, efficient purification methods, and stringent quality control to ensure the purity and efficacy of the final product.
Análisis De Reacciones Químicas
Types of Reactions: Erlotinib undergoes various chemical reactions, including:
Oxidation: this compound can be oxidized to form metabolites, primarily in the liver.
Reduction: Although less common, reduction reactions can occur under specific conditions.
Substitution: The synthesis of this compound involves multiple substitution reactions, particularly in the formation of the quinazoline core.
Common Reagents and Conditions:
Oxidation: Catalyzed by cytochrome P450 enzymes in the liver.
Substitution: Typically involves nucleophilic aromatic substitution reactions using bases like potassium carbonate.
Major Products Formed:
Oxidation Products: Metabolites such as desmethyl this compound.
Substitution Products: Intermediates with various substituents on the quinazoline ring.
Comparación Con Compuestos Similares
Erlotinib is often compared with other EGFR inhibitors such as:
Gefitinib: Another EGFR inhibitor used in the treatment of NSCLC. While both drugs target EGFR, this compound has shown higher efficacy in certain patient populations.
Afatinib: An irreversible EGFR inhibitor that also targets other members of the ErbB family. Afatinib is used for patients with specific EGFR mutations.
Osimertinib: A third-generation EGFR inhibitor effective against T790M resistance mutations. It is often used in patients who have developed resistance to first- and second-generation EGFR inhibitors.
This compound is unique in its specific inhibition of EGFR and its effectiveness in treating cancers with EGFR mutations. Its ability to improve overall survival and progression-free survival in NSCLC patients makes it a valuable option in targeted cancer therapy .
Propiedades
IUPAC Name |
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
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) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
AAKJLRGGTJKAMG-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
COCCOC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC=CC(=C3)C#C)OCCOC |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C22H23N3O4 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID8046454 |
Source
|
| Record name | Erlotinib | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8046454 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
393.4 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Erlotinib | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014671 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
Very slightly soluble (hydrochloride salt - maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2), 8.91e-03 g/L |
Source
|
| Record name | Erlotinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00530 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Erlotinib | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014671 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells., Although the exact mechanism of antineoplastic activity of erlotinib has not been fully elucidated, erlotinib appears to inhibit the intracellular phosphorylation of tyrosine kinase associated with EGFR, which is expressed on the surface of normal and cancer cells. Specificity with regard to other tyrosine kinase receptors has not been fully characterized., Erlotinib is a potent inhibitor of epidermal growth factor receptor tyrosine kinase and has been demonstrated to treat advanced or metastatic non-small cell lung cancer to prolong survival after failure of first-line or second-line chemotherapy. However, little is known about its effects on immune system. In the present study, /investigators/ aimed to investigate the immunosuppressive activity of erlotinib on T lymphocytes both in vitro and in vivo, and further explore its potential molecular mechanism. Erlotinib exerted a significant inhibition on the T cell proliferation and activation induced by concanavalin A, anti-CD3 plus anti-CD28, staphylococcal enterotoxin B or phorbol myristate acetate respectively in a concentration-dependent manner and it also inhibited the secretion of the proinflammatory cytokines such as IL-2 and IFN-gamma of activated T cells. Further study showed that erlotinib caused G0/G1 arrest and suppressed the phosphorylations of c-Raf, ERK and Akt in activated T cells. Moreover, erlotinib significantly ameliorated picryl chloride-induced ear contact dermatitis in a dose-dependent manner in vivo. In summary, these findings suggest that erlotinib may cause the impairment of T-cell-mediated immune response both in vitro and in vivo through inhibiting T cell proliferation and activation, which is closely associated with its potent down-regulation of the c-Raf/ERK cascade and Akt signaling pathway. |
Source
|
| Record name | Erlotinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00530 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Erlotinib | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8082 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
CAS No. |
183321-74-6 |
Source
|
| Record name | Erlotinib | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=183321-74-6 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Erlotinib [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0183321746 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Erlotinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00530 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Erlotinib | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8046454 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | 4-[(3-Ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/information-on-chemicals | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | ERLOTINIB | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/J4T82NDH7E | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
| Record name | Erlotinib | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8082 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Erlotinib | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014671 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Synthesis routes and methods I
Procedure details
Synthesis routes and methods II
Procedure details
Synthesis routes and methods III
Procedure details
Synthesis routes and methods IV
Procedure details
Retrosynthesis Analysis
AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.
One-Step Synthesis Focus: Specifically designed for one-step synthesis, it provides concise and direct routes for your target compounds, streamlining the synthesis process.
Accurate Predictions: Utilizing the extensive PISTACHIO, BKMS_METABOLIC, PISTACHIO_RINGBREAKER, REAXYS, REAXYS_BIOCATALYSIS database, our tool offers high-accuracy predictions, reflecting the latest in chemical research and data.
Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
Descargo de responsabilidad e información sobre productos de investigación in vitro
Tenga en cuenta que todos los artículos e información de productos presentados en BenchChem están destinados únicamente con fines informativos. Los productos disponibles para la compra en BenchChem están diseñados específicamente para estudios in vitro, que se realizan fuera de organismos vivos. Los estudios in vitro, derivados del término latino "in vidrio", involucran experimentos realizados en entornos de laboratorio controlados utilizando células o tejidos. Es importante tener en cuenta que estos productos no se clasifican como medicamentos y no han recibido la aprobación de la FDA para la prevención, tratamiento o cura de ninguna condición médica, dolencia o enfermedad. Debemos enfatizar que cualquier forma de introducción corporal de estos productos en humanos o animales está estrictamente prohibida por ley. Es esencial adherirse a estas pautas para garantizar el cumplimiento de los estándares legales y éticos en la investigación y experimentación.
