Crizotinib
説明
Historical Development and Discovery
The discovery and development of this compound represents one of the most remarkable success stories in modern oncology, characterized by an unprecedented timeline from molecular discovery to clinical application. The foundational work began in 2007 when researchers identified ALK gene rearrangements in approximately 6.7% of Japanese patients with NSCLC, specifically discovering the fusion between echinoderm microtubule-associated protein-like 4 (EML4) and the intracellular kinase domain of ALK. This pivotal discovery was published in Nature and immediately recognized as a potential therapeutic target, given the known oncogenic properties of ALK fusions previously identified in anaplastic large cell lymphoma. Remarkably, this compound had entered clinical trials one year prior to this discovery as PF-02341066, originally developed by Pfizer as a c-MET inhibitor with known activity against ALK. This fortuitous timing allowed researchers to rapidly pivot the clinical development program toward ALK-positive NSCLC patients.
The accelerated development pathway for this compound was enabled by the rapid establishment of diagnostic capabilities and patient identification strategies. Dr. John Lafrate at Massachusetts General Hospital developed the first ALK fluorescence in situ hybridization (FISH) assay using commercially available probes, enabling the screening of NSCLC tumors for ALK rearrangements. The first patient with advanced ALK-positive NSCLC was treated with this compound in December 2007, just four months after the seminal Nature publication reporting ALK rearrangements in NSCLC. This patient experienced almost immediate improvement in disease-related symptoms, validating the therapeutic potential and spurring large-scale screening efforts worldwide. The clinical development program proceeded with remarkable efficiency, with phase I and II studies demonstrating rapid and durable responses that led to accelerated FDA approval in August 2011.
The regulatory approval process for this compound established new paradigms for precision medicine development, featuring the simultaneous approval of both the therapeutic agent and its companion diagnostic test. The FDA granted accelerated approval based on objective response rates from single-arm trials rather than traditional randomized controlled studies, recognizing the urgent medical need for effective treatments in this molecularly defined patient population. This approval pathway was justified by the compelling efficacy data showing objective response rates of 50% and 61% in two pivotal single-arm trials involving 255 ALK-rearranged NSCLC patients. The accelerated approval was contingent upon conducting confirmatory phase III trials, which subsequently demonstrated superior progression-free survival compared to standard platinum-based chemotherapy regimens.
Chemical Classification and Significance
This compound belongs to the aminopyridine class of small-molecule kinase inhibitors, specifically designed to target receptor tyrosine kinases through competitive inhibition of ATP binding. The compound's systematic chemical name is (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine, reflecting its complex heterocyclic structure containing pyridine, pyrazole, and piperidine moieties. This intricate molecular architecture enables this compound to function as a multitargeted inhibitor with activity against anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (c-MET), ROS1 oncogene, and macrophage-stimulating protein receptor (RON). The drug's multitargeted profile distinguishes it from highly selective kinase inhibitors, providing therapeutic advantages in cancers driven by multiple oncogenic pathways while potentially increasing the risk of off-target effects.
The pharmacological classification of this compound places it within the L01ED01 category according to the Anatomical Therapeutic Chemical (ATC) classification system, specifically designating it as an anaplastic lymphoma kinase inhibitor within the broader category of protein kinase inhibitors. This classification reflects its primary therapeutic mechanism and distinguishes it from other kinase inhibitor subclasses such as EGFR inhibitors or BCR-ABL inhibitors. The drug's chemical properties significantly influence its pharmacokinetic profile, with a molecular weight of 450.34 daltons and specific physicochemical characteristics that affect absorption, distribution, metabolism, and excretion. This compound exhibits pH-dependent solubility, with solubility decreasing dramatically from greater than 10 mg/mL at pH 1.6 to less than 0.1 mg/mL at pH 8.2, necessitating careful consideration of formulation strategies and potential drug interactions.
The structural significance of this compound extends beyond its immediate therapeutic applications, as it has served as a template for developing next-generation ALK inhibitors designed to overcome resistance mechanisms. The compound's binding mode within the ALK kinase domain has been extensively characterized through crystallographic studies, revealing critical molecular interactions that inform structure-activity relationships. These insights have guided the rational design of second- and third-generation ALK inhibitors such as alectinib, ceritinib, and lorlatinib, which exhibit improved potency, selectivity, and resistance profiles compared to this compound. The chemical scaffold of this compound has also been modified to enhance blood-brain barrier penetration, addressing a significant limitation of the parent compound in treating central nervous system metastases.
General Molecular Overview
The molecular formula of this compound is C₂₁H₂₂Cl₂FN₅O, with a molecular weight of 450.34 daltons and CAS registry number 877399-52-5. The compound exists as a white to pale yellow crystalline powder with distinctive physicochemical properties that influence its pharmaceutical behavior and therapeutic efficacy. This compound contains two ionizable centers with pKa values of 9.4 for the piperidinium cation and 5.6 for the pyridinium cation, creating a zwitterionic character under physiological conditions that affects its solubility, permeability, and protein binding characteristics. The log partition coefficient (octanol/water) at pH 7.4 is 1.65, indicating moderate lipophilicity that facilitates cellular uptake while maintaining sufficient aqueous solubility for systemic distribution.
| Chemical Property | Value | Significance |
|---|---|---|
| Molecular Formula | C₂₁H₂₂Cl₂FN₅O | Complex heterocyclic structure |
| Molecular Weight | 450.34 daltons | Optimal for oral bioavailability |
| CAS Number | 877399-52-5 | Unique chemical identifier |
| pKa Values | 9.4, 5.6 | Ionization behavior at physiological pH |
| LogP (pH 7.4) | 1.65 | Moderate lipophilicity |
| Plasma Protein Binding | 91% | High protein binding |
| Bioavailability | 43% (32-66%) | Moderate oral absorption |
The stereochemistry of this compound is defined by the (R)-configuration at the chiral center connecting the dichlorofluorophenyl group to the ethoxy linker, which is crucial for its biological activity and receptor binding affinity. This specific stereochemical arrangement enables optimal interactions with the ATP-binding pocket of target kinases, particularly ALK, where the compound binds in an inactive conformation that prevents kinase activation. The three-dimensional structure of this compound features distinct pharmacophoric elements including the aminopyridine head group that forms hydrogen bonds with the kinase hinge region, the central pyrazole linker that provides structural rigidity, and the substituted phenyl tail group that occupies hydrophobic binding pockets.
The molecular targets of this compound extend beyond ALK to include several other receptor tyrosine kinases, creating a multitargeted inhibition profile that contributes to its therapeutic efficacy. Primary targets include ALK with IC₅₀ values of 5-20 nM, c-MET with similar potency, and ROS1 with comparable inhibitory activity. Secondary targets include the macrophage-stimulating protein receptor (RON) and potentially other kinases, though at higher concentrations that may not be clinically relevant. The selectivity profile of this compound has been extensively characterized through kinase profiling studies, revealing its preference for specific kinase subfamilies while demonstrating minimal activity against most other protein kinases in the human kinome. This selectivity pattern contributes to the drug's favorable safety profile while enabling effective inhibition of oncogenic signaling pathways in ALK-positive tumors.
特性
IUPAC Name |
3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
KTEIFNKAUNYNJU-GFCCVEGCSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(C1=C(C=CC(=C1Cl)F)Cl)OC2=C(N=CC(=C2)C3=CN(N=C3)C4CCNCC4)N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
C[C@H](C1=C(C=CC(=C1Cl)F)Cl)OC2=C(N=CC(=C2)C3=CN(N=C3)C4CCNCC4)N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C21H22Cl2FN5O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID701009329 |
Source
|
| Record name | Crizotinib | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID701009329 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
450.3 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Solubility |
Insoluble |
Source
|
| Record name | Crizotinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08865 | |
| 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. |
877399-52-5 |
Source
|
| Record name | Crizotinib | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=877399-52-5 | |
| 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 | Crizotinib [USAN:INN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0877399525 | |
| 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 | Crizotinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08865 | |
| 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 | Crizotinib | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID701009329 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine | |
| 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 | CRIZOTINIB | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/53AH36668S | |
| 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. | |
準備方法
合成ルートと反応条件： クリゾチニブの合成は、重要な中間体の調製から始まる複数の手順を必要とします。 1つの方法は、N-保護4-（3-（5-フルオロ-6-ニトロピリジン-3-イル）-1H-ピラゾール-1-イル）ピペリジンとキラル中間体を反応させて、重要なキラル中間体を得ることです。 この中間体はその後、還元され、脱保護されてクリゾチニブが得られます . 反応条件は通常穏やかであり、プロセスは大規模生産のために設計されています .
工業生産方法： クリゾチニブの工業生産は、しばしばカプセルの調製を伴います。一般的な方法には、クリゾチニブと予製デンプン、カルボキシメチルセルロースナトリウム、エアロジル、ステアリン酸マグネシウムを混合することが含まれます。 この混合物はその後、カプセル化され、薬物の溶解速度とバイオアベイラビリティが向上します .
化学反応の分析
科学研究への応用
クリゾチニブは、化学、生物学、医学の分野において、幅広い科学研究への応用を有しています。 クリゾチニブは、ALK陽性腫瘍とROS1陽性腫瘍に対する効果を研究するために、癌研究で広く使用されています. さらに、クリゾチニブは、さまざまな癌における化学療法抵抗性を克服する可能性を示しており、腫瘍学研究における貴重なツールとなっています.
科学的研究の応用
Non-Small Cell Lung Cancer (NSCLC)
Crizotinib is primarily indicated for patients with metastatic NSCLC who have confirmed ALK or ROS1 rearrangements. The drug has demonstrated substantial efficacy, leading to its FDA approval in 2011 for ALK-positive NSCLC and in 2016 for ROS1-positive NSCLC .
Efficacy Data:
- Objective Response Rate (ORR): In a large-scale trial (PROFILE 1005), this compound achieved an ORR of 54% in ALK-positive NSCLC patients .
- Progression-Free Survival (PFS): A phase III study (PROFILE 1014) showed that this compound significantly improved PFS compared to standard chemotherapy, with a median PFS of 11.1 months versus 6.8 months for chemotherapy .
| Study | Population | ORR (%) | Median PFS (months) | Common AEs |
|---|---|---|---|---|
| PROFILE 1005 | ALK-positive NSCLC | 54 | N/A | Vision disorder, nausea |
| PROFILE 1014 | Previously untreated ALK-positive | N/A | 11.1 | Increased transaminases, diarrhea |
Anaplastic Large Cell Lymphoma (ALCL)
This compound is also utilized in treating ALK-positive anaplastic large cell lymphoma. Case studies indicate significant responses in patients with this rare type of lymphoma, reinforcing its role as a treatment option .
Case Study: Dramatic Response in NSCLC
A notable case involved a female patient with NSCLC harboring an ARL1-MET fusion who was treated off-label with this compound. After three weeks, her symptoms improved significantly, and imaging showed marked tumor reduction. However, the disease eventually progressed after several months, indicating potential resistance mechanisms .
Case Study: ROS1-Positive NSCLC
In another case involving patients with ROS1-positive metastatic NSCLC, this compound demonstrated an ORR of 66% in a clinical trial setting. This trial highlighted the drug's effectiveness across various lines of therapy and contributed to its expanded indication by the FDA .
Comparative Studies
Recent studies have compared this compound to newer agents such as ensartinib and lorlatinib. These studies suggest that while this compound remains effective, newer agents may offer improved progression-free survival rates and better management of central nervous system metastases.
| Drug | Median PFS (months) | Notes |
|---|---|---|
| This compound | 12.7 | Standard treatment for ALK-positive NSCLC |
| Ensartinib | Not reached | Superior efficacy in recent trials |
| Lorlatinib | Improved | Better intracranial activity compared to this compound |
作用機序
類似化合物との比較
Ceritinib (LDK378)
- Efficacy : Ceritinib shows ORR of 56–72% in ALK-positive NSCLC, including cases resistant to this compound. Median PFS is 16.6 months in first-line use, outperforming this compound .
- Resistance : Effective against this compound-resistant mutations (e.g., F1174L) but less so against G1202R .
- Brain Metastasis : Superior CNS penetration compared to this compound, with intracranial ORR of 45% .
Alectinib (CH5424802)
Brigatinib (AP26113)
- Efficacy : ORR of 54% in this compound-resistant patients, with median PFS of 16.7 months .
- Unique Activity : Targets EGFR co-mutations, broadening its therapeutic scope .
Third-Generation ALK Inhibitors: Lorlatinib
- Efficacy : ORR of 48% in heavily pretreated patients, with intracranial ORR of 60% .
- Resistance : Overcomes most this compound-resistant mutations, including G1202R, via macrocyclic structural modifications .
ROS1 Inhibitors and Cross-Efficacy
This compound is a cornerstone in ROS1-rearranged NSCLC, outperforming chemotherapy with ORR of 85.7% vs. 44% and median PFS of 18.0 vs. 7.0 months . Comparatively, Entrectinib (a third-generation TKI) shows similar ROS1 efficacy but enhanced CNS activity .
Resistance Profiles and Mechanisms
- This compound Resistance : Driven by ALK mutations (30%), bypass signaling (e.g., EGFR), or pharmacokinetic failure (e.g., brain metastases) .
- Second-Generation TKIs : Address ALK mutations but face new resistance (e.g., ALK G1202R with Ceritinib) .
Real-World Efficacy vs Clinical Trial Data
Real-world studies confirm this compound’s consistency, with ORR of 66% and 1-year survival rates of 77–81%, aligning with trial data . However, crossover in trials complicates overall survival (OS) comparisons; this compound improved 2-year survival to 54% vs. 12% in historical controls .
Table 1: Efficacy Comparison of ALK/ROS1 Inhibitors in NSCLC
| Drug | Target | ORR (%) | Median PFS (Months) | CNS Activity | Key Resistance Mutations Addressed |
|---|---|---|---|---|---|
| This compound | ALK, ROS1 | 60–74 | 7.0–10.0 | Limited | None (baseline) |
| Ceritinib | ALK | 56–72 | 16.6 | Moderate | L1196M, F1174L |
| Alectinib | ALK | 82.9 | 34.8 | High | L1196M, C1156Y |
| Lorlatinib | ALK | 48 | Not reported | High | G1202R, L1196M |
| Entrectinib | ROS1 | 77 | 19.0 | High | ROS1 G2032R |
Table 2: Real-World Outcomes of this compound in ALK+ NSCLC
| Study Parameter | Result |
|---|---|
| Overall Response Rate (ORR) | 66% (69% first-line, 60% later-line) |
| Median PFS | 14 months |
| 1-Year Survival Rate | 77–81% |
| Median OS | 25.2 months |
生物活性
Crizotinib, a small-molecule tyrosine kinase inhibitor, is primarily recognized for its efficacy in treating non-small cell lung cancer (NSCLC) harboring ALK (anaplastic lymphoma kinase) rearrangements. However, recent research has unveiled its diverse biological activities beyond oncology, including antibacterial properties and effects on cancer metastasis. This article explores the biological activity of this compound, supported by detailed data tables and case studies.
This compound functions by inhibiting multiple tyrosine kinases, including ALK and MET. Its mechanism involves binding to the ATP-binding site of these kinases, thereby blocking their phosphorylation and subsequent signaling pathways that promote tumor growth and survival.
Key Mechanisms:
- ALK Inhibition : this compound specifically inhibits ALK phosphorylation, leading to reduced cell proliferation in ALK-positive NSCLC cells with an IC50 ranging from 250 to 340 nmol/L .
- MET Inhibition : It also targets MET, which is involved in cell growth and migration, further contributing to its antitumor effects .
Antibacterial Activity
Recent studies have highlighted this compound's unexpected antibacterial properties against Gram-positive bacteria. A notable study demonstrated that this compound exhibits significant antibacterial activity against drug-resistant strains, particularly Staphylococcus aureus.
Study Findings:
- Efficacy : this compound increased the survival rate in infected mice and reduced pulmonary inflammation .
- Mechanism : The antibacterial effect was attributed to the inhibition of ATP production and disruption of pyrimidine metabolism by targeting CTP synthase PyrG .
Antimetastatic Activity
This compound has also been shown to inhibit cancer metastasis through its effects on TGFβ signaling pathways. This is particularly relevant for NSCLC cells where metastasis poses a significant challenge.
Research Insights:
- TGFβ Inhibition : this compound suppresses TGFβ signaling by blocking Smad phosphorylation, which is crucial for cell migration and invasion .
- In Vivo Studies : Bioluminescence imaging indicated that this compound significantly reduced the metastatic capacity of NSCLC cells .
Case Studies
- Case Study on NSCLC Treatment :
- Antimicrobial Efficacy Case Study :
Q & A
Basic Research Questions
Q. What is the primary mechanism of action of crizotinib in ALK-positive non-small cell lung cancer (NSCLC), and how is this validated experimentally?
- Methodological Answer : this compound inhibits anaplastic lymphoma kinase (ALK) tyrosine kinase activity, disrupting downstream signaling pathways (e.g., STAT3, PI3K/AKT). Validation involves:
- In vitro kinase assays to measure IC50 values .
- Immunoblotting to assess phosphorylation status of ALK and downstream targets in cell lines .
- Xenograft models to evaluate tumor regression and progression-free survival .
Q. Which biomarkers are critical for identifying this compound-responsive populations, and how are they standardized across studies?
- Methodological Answer :
- Biomarkers : ALK rearrangement via FISH (break-apart probes) or RT-PCR for EML4-ALK fusion variants .
- Standardization : Use validated protocols (e.g., Vysis ALK Break Apart FISH Probe Kit) and cross-validate with immunohistochemistry (IHC) for ALK protein overexpression .
- Pitfalls : False positives in FISH due to chromosomal polysomy; confirm with orthogonal methods .
Advanced Research Questions
Q. How can contradictory clinical data on this compound resistance mechanisms be systematically analyzed?
- Methodological Answer :
- Data Integration : Combine genomic (e.g., ALK secondary mutations like L1196M), transcriptomic (upregulation of EGFR/MET), and pharmacodynamic data (e.g., drug penetration in CNS) .
- In Silico Modeling: Use molecular dynamics simulations to predict mutation-induced conformational changes in ALK that reduce this compound binding .
Q. What experimental designs are optimal for evaluating this compound’s off-target effects in preclinical models?
- Methodological Answer :
- Kinome-Wide Profiling : Use platforms like DiscoverX KINOMEscan to assess selectivity across 468 kinases .
- Phenotypic Screening : Monitor organoid viability and mitochondrial toxicity in non-cancer tissues (e.g., hepatocytes) .
- Dose Escalation : Compare clinical plasma concentrations (Cmax ≈ 300 nM) to off-target IC50 values .
Q. How can computational methods (e.g., DFT, molecular docking) enhance structural optimization of this compound analogs?
- Methodological Answer :
- DFT Calculations : Analyze electron density maps to identify regions for chemical modification (e.g., piperidine ring substitutions) .
- Docking Simulations : Use AutoDock Vina to predict binding poses with mutant ALK variants and prioritize synthetic targets .
- Table: Key Spectroscopic Parameters for this compound Structural Analysis
| Method | Key Findings | Reference |
|---|---|---|
| IR Spectroscopy | C=O stretch at 1680 cm⁻¹ confirms carbonyl group | |
| ECD | Positive Cotton effect at 290 nm indicates chiral centers |
Methodological Frameworks
Q. What strategies ensure reproducibility in this compound pharmacology studies?
- Answer :
- Compound Characterization : Provide HPLC purity (>98%), NMR/HRMS data, and batch-specific activity in supplemental materials .
- In Vivo Protocols: Adopt ARRIVE guidelines for tumor volume measurements and survival endpoints .
Q. How should researchers address discrepancies between in vitro and clinical efficacy data?
- Answer :
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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