molecular formula C24H25ClFN5O3 B000358 Afatinib CAS No. 439081-18-2

Afatinib

Cat. No.: B000358
CAS No.: 439081-18-2
M. Wt: 485.9 g/mol
InChI Key: ULXXDDBFHOBEHA-CWDCEQMOSA-N
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Description

Afatinib is a medication used primarily for the treatment of non-small cell lung cancer (NSCLC)This compound is effective against tumors that harbor mutations in the EGFR gene, which are often found in NSCLC .

Scientific Research Applications

Afatinib has a wide range of scientific research applications, including:

Mechanism of Action

Target of Action

Afatinib is an oral, irreversible ErbB family blocker . It primarily targets the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4 . These receptors are part of the ErbB family, which includes four different cancer cell epidermal growth factor receptors: EGFR, HER2, ErbB3, and ErbB4 . These receptors play a crucial role in the regulation of cell growth and survival .

Mode of Action

This compound works by covalently binding to and irreversibly blocking signaling from all homo and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4 . This results in irreversible inhibition of tyrosine kinase autophosphorylation . This compound’s interaction with its targets leads to the suppression of the proliferation of cancer cells .

Biochemical Pathways

This compound affects the biochemical pathways related to the ErbB family of receptors. By inhibiting the tyrosine kinase autophosphorylation of these receptors, this compound disrupts the signaling pathways that promote cell growth and survival . Additionally, this compound has been shown to exert immunomodulatory effects by targeting the pyrimidine biosynthesis enzyme CAD .

Pharmacokinetics

This compound demonstrates time-independent pharmacokinetic characteristics . After oral administration, maximum plasma concentrations of this compound are reached approximately 2–5 hours post-dose . This compound exposure increases slightly more than dose-proportionally over the clinical dose range of 20–50 mg . This compound metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5% in urine . The effective elimination half-life is approximately 37 hours .

Result of Action

The molecular and cellular effects of this compound’s action include the suppression of CD8+ T lymphocyte proliferation and the inhibition of cellular growth and induction of apoptosis in a wide range of cells representative for non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network .

Action Environment

Environmental factors such as age, ethnicity, smoking status, and hepatic function have no influence on this compound pharmacokinetics . Females and patients with low body weight have increased exposure to this compound . Renal function is correlated with this compound exposure . This compound has a low potential for drug–drug interactions, especially with cytochrome P450-modulating agents . Concomitant treatment with potent inhibitors or inducers of the p-glycoprotein transporter can affect the pharmacokinetics of this compound .

Safety and Hazards

Afatinib may cause anemia, cough, CNS depression, drowsiness, headache, heart damage, lassitude (weakness, exhaustion), liver damage, narcosis, reproductive effects, teratogenic effects . It is considered hazardous by the 2012 OSHA Hazard Communication Standard (29 CFR 1910.1200) with acute oral toxicity, skin corrosion/irritation, serious eye damage/eye irritation, specific target organ toxicity (single exposure) with target organs being the respiratory system .

Future Directions

Different from the LL3-LL6 joint analysis, prespecified subgroup analyses showed a similar OS trends (afatinib versus gefitinib) in patients with an exon 19 deletion [30.7 versus 26.4 months; HR: 0.83 (95% CI: 0.58–1.17), p = 0.2841] and L858R mutations [25.0 versus 21.2 months; HR 0.91, (95% CI 0.62–1.36), p = 0.6585], suggesting that an exon 19 deletion identifies a subgroup of patients with a different natural history and a better sensitivity to EGFR TKIs .

Preparation Methods

Synthetic Routes and Reaction Conditions

The synthesis of afatinib involves several key steps, starting with the preparation of the quinazoline core. One common method involves the use of 2-nitrile-4-[4-(N,N-dimethylamino)-I-oxo-2-buten-I-yl]amino-5-[(S)-(tetrahydrofuran-3-yl)oxy]aniline and 4-fluoro-3-chloroaniline as starting materials. These compounds undergo condensation and cyclization reactions in the presence of N,N-dimethylformamide dimethyl acetal to form this compound .

Industrial Production Methods

For industrial production, the synthesis of this compound is optimized to reduce manufacturing steps and lower costs. The process involves modifying functional groups at specific positions on the quinazoline nucleus, followed by a series of reactions including cyclization, nitration, substitution, reduction, condensation, and salification. This method yields this compound with high purity and is suitable for large-scale production .

Chemical Reactions Analysis

Types of Reactions

Afatinib undergoes various chemical reactions, including:

    Oxidation: this compound can be oxidized under specific conditions to form different metabolites.

    Reduction: Reduction reactions can modify the functional groups on this compound, potentially altering its activity.

    Substitution: Substitution reactions can occur at various positions on the quinazoline ring, leading to the formation of different derivatives.

Common Reagents and Conditions

    Oxidation: Common oxidizing agents include hydrogen peroxide and potassium permanganate.

    Reduction: Reducing agents such as sodium borohydride and lithium aluminum hydride are used.

    Substitution: Reagents like halogens and nucleophiles are used under controlled conditions to achieve substitution reactions.

Major Products

The major products formed from these reactions include various metabolites and derivatives of this compound, which may have different pharmacological properties .

Comparison with Similar Compounds

Afatinib is often compared with other tyrosine kinase inhibitors such as erlotinib, gefitinib, and osimertinib. While all these compounds target EGFR, this compound is unique in its ability to irreversibly inhibit multiple members of the EGFR family, including HER2 and HER4. This broader spectrum of activity makes this compound effective against a wider range of EGFR mutations, including some that are resistant to first-generation inhibitors .

Similar Compounds

This compound’s unique mechanism of action and broader spectrum of activity make it a valuable option in the treatment of NSCLC and other cancers with EGFR mutations.

Properties

IUPAC Name

(E)-N-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI

InChI=1S/C24H25ClFN5O3/c1-31(2)8-3-4-23(32)30-21-11-17-20(12-22(21)34-16-7-9-33-13-16)27-14-28-24(17)29-15-5-6-19(26)18(25)10-15/h3-6,10-12,14,16H,7-9,13H2,1-2H3,(H,30,32)(H,27,28,29)/b4-3+/t16-/m0/s1
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI Key

ULXXDDBFHOBEHA-CWDCEQMOSA-N
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Canonical SMILES

CN(C)CC=CC(=O)NC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)OC4CCOC4
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Isomeric SMILES

CN(C)C/C=C/C(=O)NC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)O[C@H]4CCOC4
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Molecular Formula

C24H25ClFN5O3
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

DSSTOX Substance ID

DTXSID20893451
Record name Afatinib
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Molecular Weight

485.9 g/mol
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Mechanism of Action

Afatinib is a potent and selective, irreversible ErbB family blocker. Afatinib covalently binds to and irreversibly blocks signaling from all homo and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. In particular, afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods. The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions. Moreover, afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2.
Record name Afatinib
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CAS No.

850140-72-6, 439081-18-2
Record name Afatinib
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Record name Afatinib
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Record name Afatinib
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Record name Afatinib
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Retrosynthesis Analysis

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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

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Customer
Q & A

A: Afatinib irreversibly binds to and inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER4. [, , ] This irreversible binding distinguishes it from first-generation EGFR tyrosine kinase inhibitors (TKIs) like gefitinib and erlotinib. [, ]

A: By inhibiting EGFR, HER2, and HER4, this compound disrupts downstream signaling pathways crucial for tumor cell proliferation, survival, and angiogenesis. [, ] Specifically, it inhibits the phosphorylation of EGFR, HER2, Akt, and Erk, leading to cell cycle arrest, apoptosis, and suppression of tumor growth. [, , ]

ANone: Spectroscopic data for this compound, including nuclear magnetic resonance (NMR) and mass spectrometry (MS) information, was not found in the provided research articles. For detailed spectroscopic data, it's recommended to consult comprehensive chemical databases or the manufacturer's drug information.

A: this compound is a kinase inhibitor, not a catalyst. It works by competitively binding to the ATP-binding site of tyrosine kinases, preventing their catalytic activity. [, ]

A: Encapsulation of this compound into polymeric micelles has been shown to improve its delivery and cytotoxic activity in vitro and in vivo. [] This formulation strategy suggests potential for enhancing this compound's stability, solubility, or bioavailability. Further research is needed to fully understand the impact of various formulation strategies on this compound's pharmacokinetic properties.

ANone: The provided research articles primarily focus on this compound's preclinical and clinical efficacy and safety. Information regarding SHE regulations, risk minimization, and responsible practices during its development and manufacturing is not readily available in these articles. Consulting regulatory agency guidelines and the manufacturer's documentation would provide more information on SHE compliance.

A: The irreversible binding of this compound to its targets potentially leads to a prolonged duration of action compared to reversible TKIs. [, ] This property was demonstrated in a mouse model of EGFR-driven lung cancer, where this compound suppressed tumor growth and induced apoptosis for a longer duration than gefitinib. [] Further research is needed to fully elucidate the relationship between its irreversible binding and its PK/PD profile in humans.

A: this compound demonstrates antitumor activity in various preclinical models, including cell lines and xenografts. [, , , ] In vitro studies showed that it inhibits the proliferation of several cancer cell lines, including those harboring EGFR mutations, HER2 overexpression, and those with acquired resistance to other EGFR TKIs. [, , ]

A: In vivo studies in mice have shown that this compound effectively suppresses tumor growth in xenograft models of lung cancer, including those with EGFR mutations and acquired resistance to first-generation TKIs. [, ] Additionally, this compound-encapsulated micelles exhibited superior tumor growth suppression compared to this compound alone in a HER2-overexpressing xenograft model. []

A: Clinical trials have demonstrated that this compound is effective in treating EGFR mutation-positive non-small cell lung cancer (NSCLC). [, , , ] In the LUX-Lung 3 and LUX-Lung 6 trials, this compound significantly improved progression-free survival compared to standard chemotherapy in patients with EGFR mutation-positive NSCLC. [, ] Further, a phase II trial showed that this compound monotherapy demonstrated activity in patients with HER2-positive metastatic breast cancer after progression on trastuzumab. []

A: Despite its initial effectiveness, acquired resistance to this compound can develop. Several mechanisms have been identified, including the emergence of the EGFR T790M secondary mutation [, , , ], MET amplification [, ], activation of the insulin-like growth factor 1 receptor (IGF1R) signaling pathway [], upregulation of secreted phosphoprotein 1 (SPP1) [], and activation of fibroblast growth factor receptor 1 (FGFR1). []

A: While this compound can overcome resistance to first-generation EGFR TKIs mediated by the T790M mutation, cross-resistance can still occur through alternative mechanisms. [, , ] For instance, acquired resistance to the anti-EGFR monoclonal antibody ICR62 can lead to cross-resistance to this compound in colorectal cancer cells. []

A: Clinical trials have shown that this compound is generally well tolerated, although it can cause adverse events, primarily related to its inhibition of EGFR in skin and gastrointestinal tissues. [, , ] Dose reductions may be necessary to manage these side effects. [] For detailed safety information, it's crucial to refer to the product label and clinical trial data.

A: Encapsulation of this compound into polymeric micelles has been shown to enhance its delivery to cancer cells and improve its cytotoxic activity. [] This approach suggests potential for improving this compound's therapeutic index by increasing its concentration at tumor sites while minimizing off-target effects.

A: Various analytical methods have been employed to characterize this compound and assess its activity, including cell viability assays (e.g., MTT assay), flow cytometry (for cell cycle and apoptosis analysis), Western blot analysis (for protein expression), and next-generation sequencing (for mutation analysis). [, , , ]

ANone: The provided research articles primarily focus on this compound's preclinical and clinical aspects. Information about its ecotoxicological effects, degradation pathways, and environmental fate is not readily available in these articles. Further research is needed to address these environmental considerations.

ANone: Specific studies focusing on this compound's dissolution rate and solubility in various media were not found in the provided research articles. This information is important for understanding its bioavailability and formulating effective drug products.

ANone: While the research articles employ various analytical techniques, details about their validation, including accuracy, precision, and specificity, are not consistently provided. Validating analytical methods is crucial for ensuring the reliability and reproducibility of research findings.

ANone: Information about specific quality control and assurance measures implemented during this compound's development, manufacturing, and distribution was not found in the provided research articles.

ANone: The provided research articles primarily focus on this compound's anti-tumor activity and do not address its potential immunogenicity. Further research is needed to investigate whether this compound can elicit an immune response and explore strategies to mitigate or modulate any potential immunogenicity.

ANone: The provided research articles do not contain information about this compound's interactions with drug transporters. Understanding such interactions is important for predicting drug disposition and potential drug-drug interactions.

ANone: The provided research articles do not provide details about this compound's potential to induce or inhibit drug-metabolizing enzymes. Investigating these interactions is crucial for assessing potential drug-drug interactions and optimizing this compound's therapeutic use.

ANone: The provided research articles primarily focus on this compound's efficacy and safety in treating cancer. Information regarding its biocompatibility with various biological systems and its potential for biodegradation was not found in these articles. Further research is needed to address these aspects, particularly for exploring alternative delivery systems and minimizing potential environmental impact.

A: Combination therapies, such as this compound plus cetuximab, have shown promise in delaying resistance compared to single-agent TKIs. [, ] Additionally, combining this compound with chemotherapy agents like vinorelbine has been explored in clinical trials. [, ]

ANone: The provided research articles primarily focus on this compound's therapeutic aspects. Information regarding specific strategies for recycling this compound or managing its waste was not found in these articles. Addressing these issues is important for promoting sustainable practices in pharmaceutical development and use.

ANone: Various research infrastructures and resources are crucial for advancing our understanding of this compound, including:

  • Preclinical models: Cell lines and xenograft models are valuable tools for studying this compound's efficacy and resistance mechanisms. [, , , ]

A: The development of this compound represents a significant milestone in targeted cancer therapy, particularly for EGFR mutation-positive NSCLC. Initial research focused on its preclinical activity and potential to overcome resistance to first-generation EGFR TKIs. [, ] Subsequent clinical trials established its efficacy and safety as a first-line treatment for EGFR mutation-positive NSCLC. [, , , ] Current research is exploring its use in other cancer types, combination therapies, and strategies to address acquired resistance.

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