Osimertinib
概要
説明
オシメルチニブは、アストラゼネカ製薬が開発した第3世代上皮成長因子受容体（EGFR）チロシンキナーゼ阻害剤（TKI）です。 主に、EGFR遺伝子にT790M変異などの特定の変異を有する非小細胞肺がん（NSCLC）の治療に使用されます . オシメルチニブは、EGFR遺伝子の感受性変異と耐性変異の両方を選択的に標的化する能力で知られており、NSCLCの管理において重要な薬剤です .
作用機序
オシメルチニブは、T790M、L858R、エクソン19欠失変異など、EGFRの変異型に不可逆的に結合することで効果を発揮します . この結合は、受容体のチロシンキナーゼ活性を阻害し、細胞増殖と生存を促進する下流のシグナル伝達経路を阻止します . オシメルチニブは、血液脳関門を通過する能力もあり、脳転移の治療にも効果的です .
類似の化合物との比較
類似の化合物
ゲフィチニブ： NSCLCの治療に使用される第1世代EGFR TKIです。
エルロチニブ： ゲフィチニブと同様の制限がある、別の第1世代EGFR TKIです.
アファチニブ： より強力ですが、毒性がより高い第2世代EGFR TKIです.
オシメルチニブの独自性
オシメルチニブは、EGFR遺伝子の感受性変異と耐性変異の両方を選択的に標的化する一方で、野生型EGFRを温存することで毒性を軽減する、という点で独特です . T790M変異を伴うNSCLCの治療において優れた有効性を示しており、以前の世代のEGFR TKIと比較して安全性のプロファイルが良好です .
生化学分析
Biochemical Properties
Osimertinib is a potent, selective, irreversible EGFR-TKI . It interacts with EGFR, a protein that plays a crucial role in cell growth and division . This compound covalently binds to EGFR C797, reducing the effect of this compound in inhibiting cell proliferation and EGFR phosphorylation .
Cellular Effects
This compound has significant effects on various types of cells and cellular processes. It influences cell function by impacting cell signaling pathways, gene expression, and cellular metabolism . This compound has been shown to significantly sensitize both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs .
Molecular Mechanism
This compound exerts its effects at the molecular level through several mechanisms. It binds irreversibly to the gate-keeper T790M mutations which increases ATP binding activity to EGFR and result in poor prognosis for late-stage disease . Furthermore, this compound has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity .
Temporal Effects in Laboratory Settings
In laboratory settings, this compound has shown changes in its effects over time. For instance, it has been observed that resistance to this compound inevitably develops during the treatment, limiting its long-term effectiveness .
Dosage Effects in Animal Models
In animal models, the effects of this compound vary with different dosages. For example, a study showed that this compound significantly inhibited tumor growth in a PC9T790M xenograft model .
Metabolic Pathways
This compound is involved in several metabolic pathways. It is mainly metabolized by the CYP3A enzyme in humans . Among the metabolites produced by this compound, AZ5104, and AZ7550, which are demethylated, are most vital .
Transport and Distribution
This compound is transported and distributed within cells and tissues. It significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter .
Subcellular Localization
It has been observed that this compound significantly sensitizes both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs .
準備方法
合成経路と反応条件
オシメルチニブの合成は、市販の出発物質から始まり、複数の段階で行われます。主要な段階には、コア構造の形成、続いて様々な官能基の導入が含まれます。合成経路は通常、以下を含みます。
コア構造の形成： オシメルチニブのコア構造は、一連の縮合反応と環化反応によって合成されます。
官能基の導入： メトキシ、ジメチルアミノ、インドール基などの様々な官能基は、求核置換反応とカップリング反応によって導入されます。
最終的なアセンブリ： 最終的なアセンブリは、コア構造と側鎖をカップリングして完全な分子を形成することを含みます.
工業生産方法
オシメルチニブの工業生産には、高収率と高純度を確保するために合成経路を最適化することが含まれます。プロセスには通常、以下が含まれます。
化学反応解析
反応の種類
オシメルチニブは、以下を含む様々な化学反応を起こします。
酸化： オシメルチニブは、シトクロムP450酵素によって酸化され、水酸化代謝物の形成につながることがあります.
還元： 還元反応はあまり一般的ではありませんが、特定の条件下で起こる可能性があります。
一般的な試薬と条件
酸化： 一般的な試薬には、シトクロムP450酵素やその他の酸化剤が含まれます。
主な生成物
これらの反応から生成される主な生成物には、水酸化代謝物と脱メチル化代謝物が含まれ、主に糞便と尿によって排泄されます .
科学研究への応用
オシメルチニブは、以下を含む幅広い科学研究への応用があります。
化学： EGFR阻害と耐性のメカニズムを研究するためのモデル化合物として使用されます.
生物学： 細胞シグナル伝達経路への影響と、がん細胞のアポトーシス誘導能力について調査されています.
化学反応の分析
Types of Reactions
Osimertinib undergoes various chemical reactions, including:
Reduction: Reduction reactions are less common but can occur under specific conditions.
Common Reagents and Conditions
Oxidation: Common reagents include cytochrome P450 enzymes and other oxidizing agents.
Substitution: Reagents such as dimethylamine and methoxy groups are used in nucleophilic substitution reactions.
Major Products
The major products formed from these reactions include hydroxylated and demethylated metabolites, which are primarily excreted through feces and urine .
科学的研究の応用
Osimertinib has a wide range of scientific research applications, including:
Chemistry: Used as a model compound to study the mechanisms of EGFR inhibition and resistance.
Medicine: Primarily used in the treatment of NSCLC with specific EGFR mutations.
Industry: Used in the development of new EGFR inhibitors and combination therapies to overcome resistance.
類似化合物との比較
Similar Compounds
Gefitinib: A first-generation EGFR TKI used in the treatment of NSCLC.
Erlotinib: Another first-generation EGFR TKI with similar limitations as gefitinib.
Afatinib: A second-generation EGFR TKI that is more potent but associated with higher toxicity.
Dacomitinib: Another second-generation EGFR TKI with broader activity but increased side effects.
Uniqueness of Osimertinib
This compound is unique in its ability to selectively target both sensitizing and resistance mutations in the EGFR gene while sparing wild-type EGFR, reducing toxicity . It has shown superior efficacy in treating NSCLC with T790M mutations and has a favorable safety profile compared to earlier generations of EGFR TKIs .
特性
IUPAC Name |
N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C28H33N7O2/c1-7-27(36)30-22-16-23(26(37-6)17-25(22)34(4)15-14-33(2)3)32-28-29-13-12-21(31-28)20-18-35(5)24-11-9-8-10-19(20)24/h7-13,16-18H,1,14-15H2,2-6H3,(H,30,36)(H,29,31,32) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
DUYJMQONPNNFPI-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CN1C=C(C2=CC=CC=C21)C3=NC(=NC=C3)NC4=C(C=C(C(=C4)NC(=O)C=C)N(C)CCN(C)C)OC |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C28H33N7O2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID501025961 |
Source
|
| Record name | Osimertinib | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID501025961 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
499.6 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Mechanism of Action |
Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that binds to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) that predominate in non-small cell lung cancer (NSCLC) tumours following treatment with first-line EGFR-TKIs. As a third-generation tyrosine kinase inhibitor, osimertinib is specific for the gate-keeper T790M mutation which increases ATP binding activity to EGFR and results in poor prognosis for late-stage disease. Furthermore, osimertinib has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity. Compared to wild-type EGFR, osimertinib has 200 times higher affinity for EGFR molecules with the L858R/T790M mutation _in vitro_. |
Source
|
| Record name | Osimertinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09330 | |
| 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) | |
CAS No. |
1421373-65-0 |
Source
|
| Record name | Osimertinib | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=1421373-65-0 | |
| 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 | Osimertinib [USAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=1421373650 | |
| 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 | Osimertinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09330 | |
| 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 | Osimertinib | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID501025961 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | OSIMERTINIB | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/3C06JJ0Z2O | |
| 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. | |
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Synthesis routes and methods II
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Synthesis routes and methods III
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Q1: What is the primary target of osimertinib and how does it interact with this target?
A1: this compound is designed to irreversibly bind to EGFR, specifically targeting both EGFR-TKI-sensitizing mutations and the EGFR T790M resistance mutation. [] This covalent binding inhibits the kinase activity of EGFR. [, ]
Q2: What are the downstream effects of this compound binding to EGFR?
A2: this compound binding to EGFR blocks downstream signaling pathways, including PI3K-AKT and MAPK-ERK, crucial for cancer cell growth and survival. [, , ] This inhibition leads to decreased cell proliferation, increased apoptosis, and reduced tumor growth. [, , ]
Q3: Does this compound affect other targets besides EGFR?
A3: While highly selective for EGFR, this compound can also inhibit HER2 (ERBB2) to a lesser extent. [] This off-target effect might contribute to some of its side effects.
Q4: What is the molecular formula and weight of this compound?
A4: The provided research articles do not explicitly mention the molecular formula or weight of this compound.
Q5: Is there any spectroscopic data available for this compound in these studies?
A5: The provided research articles do not include spectroscopic data for this compound.
Q6: How stable is this compound under various storage conditions?
A6: The research articles don’t elaborate on specific stability data for this compound under various conditions.
Q7: Does this compound have any catalytic properties as described in the research?
A7: this compound acts as an inhibitor, not a catalyst. Its primary mechanism involves irreversible binding to EGFR, blocking its kinase activity rather than catalyzing a reaction.
Q8: Have any computational chemistry studies been performed on this compound?
A8: The provided research articles do not discuss computational chemistry studies conducted on this compound.
Q9: How do structural modifications of this compound impact its activity and selectivity?
A9: The research articles primarily focus on this compound itself and do not delve into the SAR of the compound through structural modifications.
Q10: Are there any specific formulation strategies used to improve the stability, solubility, or bioavailability of this compound?
A10: The research articles do not provide details on the formulation strategies employed for this compound.
Q11: Do the articles mention any specific SHE regulations regarding this compound development or manufacturing?
A11: The provided research articles primarily focus on the clinical and biological aspects of this compound and do not explicitly discuss SHE regulations.
Q12: How is this compound absorbed, distributed, metabolized, and excreted (ADME) in the body?
A12: this compound is primarily metabolized by CYP3A enzymes. [] Following oral administration, it is extensively distributed throughout the body and eliminated mainly through the fecal route. []
Q13: Does food or gastric pH affect the pharmacokinetics of this compound?
A13: Research indicates that co-administration with food or omeprazole, a gastric pH modifier, does not significantly impact the exposure of this compound. []
Q14: What in vitro models have been used to study this compound efficacy?
A14: Various EGFR-mutant NSCLC cell lines, including H1975, PC-9, HCC827, and HCC4006, have been utilized to investigate the efficacy of this compound in vitro. [, , , , ]
Q15: What in vivo models have been used to assess this compound's efficacy?
A15: this compound's effectiveness has been evaluated in vivo using xenograft and patient-derived xenograft (PDX) models of EGFR-mutant NSCLC. [, , , ] These models help to understand the drug's impact on tumor growth and metastasis.
Q16: Have clinical trials been conducted to evaluate the efficacy of this compound?
A16: Yes, several clinical trials, including the FLAURA and AURA3 trials, have demonstrated the efficacy of this compound in treating EGFR-mutant NSCLC. [, , , , , , , ]
Q17: What is the efficacy of this compound against brain metastases?
A17: this compound demonstrates efficacy against brain metastases, as observed in clinical trials and case studies. [, , , ] It shows promising activity in controlling tumor growth and improving progression-free survival in patients with EGFR-mutant NSCLC with brain metastases.
Q18: Can this compound be combined with other therapies for enhanced efficacy?
A18: Research suggests potential synergistic effects when this compound is combined with other therapies like bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF). [, , ]
Q19: What are the known mechanisms of resistance to this compound?
A19: Several resistance mechanisms to this compound have been identified, including: * EGFR-dependent mechanisms: The emergence of the EGFR C797S mutation is a significant mechanism of acquired resistance. [, ] * EGFR-independent mechanisms: These include MET amplification, epithelial-to-mesenchymal transition (EMT), AXL upregulation, HER2 amplification, and mutations in KRAS, BRAF, and PIK3CA. [, , , , , ]
Q20: Is there any evidence of cross-resistance between this compound and other anticancer drugs?
A20: While not extensively discussed in the provided articles, research suggests that resistance mechanisms like MET amplification can confer cross-resistance to multiple TKIs, including this compound. [, ]
Q21: What are the common adverse events associated with this compound treatment?
A21: Common adverse events reported with this compound include paronychia, QTc prolongation, and gastrointestinal issues like diarrhea. [, , ]
Q22: Are there any specific cardiac safety concerns associated with this compound?
A22: QTc prolongation is a known cardiac safety concern with this compound. [, ] Additionally, cases of congestive heart failure and decreased left ventricular ejection fraction have been reported, emphasizing the need for cardiac monitoring during treatment. [, ]
Q23: Are there any specific drug delivery systems or targeting strategies being explored to enhance this compound delivery to tumor sites?
A23: The provided research articles do not delve into specific drug delivery systems or targeting strategies for this compound.
Q24: What analytical techniques are used to measure this compound and its metabolites in biological samples?
A24: Ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) is commonly used to quantify this compound and its metabolites in biological samples. [, ]
Q25: Are there any specific techniques used for detecting resistance mechanisms like EGFR mutations?
A25: Next-generation sequencing (NGS) is widely employed to detect EGFR mutations, including T790M and C797S, which are crucial for predicting this compound response and monitoring resistance. [, , , ]
Q26: Do the research articles address the environmental impact or degradation of this compound?
A26: The provided research articles focus on clinical and biological aspects of this compound and do not discuss its environmental impact or degradation.
Q27: What is known about the dissolution rate and solubility of this compound in different media?
A27: The research articles don't provide specific details regarding the dissolution rate and solubility of this compound in various media.
Q28: Are there any details provided on the validation of analytical methods used for this compound analysis?
A28: The provided research articles do not elaborate on the validation procedures of the analytical methods used for this compound quantification.
Q29: Do the research articles mention specific quality control measures for this compound manufacturing and distribution?
A29: The research articles primarily focus on clinical research and do not delve into the specifics of quality control measures implemented during this compound manufacturing and distribution.
Q30: Is there any information on the potential of this compound to induce an immune response?
A30: The provided research articles do not discuss the potential immunogenicity of this compound.
Q31: Do the research articles provide insights into interactions between this compound and drug transporters?
A31: The research articles do not provide information on interactions between this compound and drug transporters.
Q32: Does this compound induce or inhibit drug-metabolizing enzymes?
A32: The research articles primarily focus on the metabolism of this compound by CYP3A enzymes and do not mention if this compound itself influences the activity of drug-metabolizing enzymes. [, ]
Q33: Is there any information available on the biocompatibility or biodegradability of this compound?
A33: The research articles do not provide information on the biocompatibility or biodegradability of this compound.
Q34: Are there any alternative treatments or compounds with similar mechanisms of action to this compound?
A34: Other third-generation EGFR-TKIs are being investigated, although this compound remains a prominent treatment option. [, , ] Furthermore, research explores combining this compound with other targeted therapies or chemotherapy to overcome resistance and improve outcomes. [, , , ]
Q35: Do the research articles address strategies for recycling or managing waste generated during this compound manufacturing or administration?
A35: The provided research articles do not discuss the recycling or waste management aspects associated with this compound.
Q36: Do the research articles highlight any specific research infrastructure or resources essential for this compound research?
A36: The research articles implicitly emphasize the significance of resources like:
- Cell lines and PDX models: These are vital tools for studying this compound's efficacy and investigating resistance mechanisms in vitro and in vivo. [, , , , , , ]
- NGS technology: This technology plays a crucial role in identifying genetic alterations, such as EGFR mutations, essential for predicting drug response and monitoring resistance. [, , , ]
Q37: How has the research on this compound evolved, and what are the key milestones in its development as a lung cancer treatment?
A37: this compound's development represents a significant milestone in the treatment of EGFR-mutant NSCLC, particularly for patients who develop resistance to first- and second-generation EGFR-TKIs. [, , , ] Key milestones include its initial approval for use in T790M-positive NSCLC and its subsequent approval for first-line treatment of EGFR-mutant advanced NSCLC. [, , ] Current research focuses on overcoming resistance mechanisms and improving long-term outcomes for patients.
Q38: What are some examples of cross-disciplinary research and collaboration in the development and application of this compound?
A38: this compound research involves collaboration between various disciplines, including:
- Oncology and Pharmacology: Clinicians and pharmacologists work together to evaluate the efficacy and safety of this compound in clinical trials. [, , , , , , , ]
- Molecular Biology and Genetics: Researchers investigate the molecular mechanisms of this compound action and resistance, relying on techniques like NGS to identify key genetic alterations. [, , , ]
- Biochemistry and Pharmacology: Scientists study the interactions between this compound and its target, EGFR, as well as its ADME profile. [, ]
試験管内研究製品の免責事項と情報
BenchChemで提示されるすべての記事および製品情報は、情報提供を目的としています。BenchChemで購入可能な製品は、生体外研究のために特別に設計されています。生体外研究は、ラテン語の "in glass" に由来し、生物体の外で行われる実験を指します。これらの製品は医薬品または薬として分類されておらず、FDAから任何の医療状態、病気、または疾患の予防、治療、または治癒のために承認されていません。これらの製品を人間または動物に体内に導入する形態は、法律により厳格に禁止されています。これらのガイドラインに従うことは、研究と実験において法的および倫理的な基準の遵守を確実にするために重要です。
