Everolimus
Description
Everolimus is a macrolide immunosuppressant and anticancer agent derived from sirolimus (rapamycin), a natural product of Streptomyces hygroscopicus. Structurally, this compound features a 2-hydroxyethyl chain substitution at position 40 on the sirolimus molecule, enhancing its polarity and pharmacokinetic properties compared to its parent compound . As a mammalian target of rapamycin (mTOR) inhibitor, this compound binds to the FK506-binding protein 12 (FKBP12), forming a complex that inhibits mTORC1, a critical regulator of cell growth, proliferation, and angiogenesis . Clinically, it is approved for advanced renal cell carcinoma (RCC), hormone receptor-positive/HER2-negative metastatic breast cancer, pancreatic neuroendocrine tumors (pNETs), and tuberous sclerosis complex (TSC)-associated tumors .
Properties
Key on ui mechanism of action |
Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that functions via two multiprotein complexes, namely mTORC1 and mTORC2, each characterized by different binding partners that confer separate functions. mTORC1 function is tightly regulated by PI3-K/Akt and is sensitive to rapamycin. mTORC2 is sensitive to growth factors, not nutrients, and is associated with rapamycin-insensitivity. mTORC1 regulates protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. Also, mTORC2 is thought to modulate growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases such as Akt and SGK. Recent evidence has suggested that mTORC2 may play an important role in maintenance of normal as well as cancer cells by virtue of its association with ribosomes, which may be involved in metabolic regulation of the cell. Rapamycin (sirolimus) and its analogs known as rapalogues, such as RAD001 (everolimus) and CCI-779 (temsirolimus), suppress mTOR activity through an allosteric mechanism that acts at a distance from the ATP-catalytic binding site, and are considered incomplete inhibitors. Moreover, these compounds suppress mTORC1-mediated S6K activation, thereby blocking a negative feedback loop, leading to activation of mitogenic pathways promoting cell survival and growth. Consequently, mTOR is a suitable target of therapy in cancer treatments. However, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. In recent years, new pharmacologic agents have been developed which can inhibit these complexes via ATP-binding mechanism, or dual inhibition of the canonical PI3-K/Akt/mTOR signaling pathway. These compounds include WYE-354, KU-003679, PI-103, Torin1, and Torin2, which can target both complexes or serve as a dual inhibitor for PI3-K/mTOR. This investigation describes the mechanism of action of pharmacological agents that effectively target mTORC1 and mTORC2 resulting in suppression of growth, proliferation, and migration of tumor and cancer stem cells. Mammalian target of rapamycin (mTOR) inhibitors have anti-tumor effects against renal cell carcinoma, pancreatic neuroendocrine cancer and breast cancer. In this study, we analyzed the antitumor effects of mTOR inhibitors in small cell lung cancer (SCLC) cells and sought to clarify the mechanism of resistance to mTOR inhibitors. We analyzed the antitumor effects of three mTOR inhibitors including everolimus in 7 SCLC cell lines by MTS assay. Gene-chip analysis, receptor tyrosine kinases (RTK) array and Western blotting analysis were performed to identify molecules associated with resistance to everolimus. Only SBC5 cells showed sensitivity to everolimus by MTS assay. We established two everolimus resistant-SBC5 cell lines (SBC5 R1 and SBC5 R10) by continuous exposure to increasing concentrations of everolimus stepwise. SPP1 and MYC were overexpressed in both SBC5 R1 and SBC5 R10 by gene-chip analysis. High expression levels of eukaryotic translation initiation factor 4E (eIF4E) were observed in 5 everolimus-resistant SCLC cells and SBC5 R10 cells by Western blotting. MYC siRNA reduced eIF4E phosphorylation in SBC5 cells, suggesting that MYC directly activates eIF4E by an mTOR-independent bypass pathway. Importantly, after reduction of MYC or eIF4E by siRNAs, the SBC5 parent and two SBC5-resistant cells displayed increased sensitivity to everolimus relative to the siRNA controls. These findings suggest that eIF4E has been shown to be an important factor in the resistance to everolimus in SCLC cells. Furthermore, a link between MYC and mTOR-independent eIF4E contribute to the resistance to everolimus in SCLC cells. Control of the MYC-eIF4E axis may be a novel therapeutic strategy for everolimus action in SCLC. Everolimus inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes. In cells, everolimus binds to a cytoplasmic protein, the FK506 Binding Protein-12 (FKBP-12), to form an immunosuppressive complex (everolimus: FKBP-12) that binds to and inhibits the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. In the presence of everolimus phosphorylation of p70 S6 ribosomal protein kinase (p70S6K), a substrate of mTOR, is inhibited. Consequently, phosphorylation of the ribosomal S6 protein and subsequent protein synthesis and cell proliferation are inhibited. The everolimus: FKBP-12 complex has no effect on calcineurin activity. In rats and nonhuman primate models, everolimus effectively reduces kidney allograft rejection resulting in prolonged graft survival. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies. Constitutive activation of the PI3K/Akt/mTOR pathway can contribute to endocrine resistance in breast cancer. In vitro studies show that estrogen-dependent and HER2+ breast cancer cells are sensitive to the inhibitory effects of everolimus, and that combination treatment with everolimus and Akt, HER2, or aromatase inhibitors enhances the anti-tumor activity of everolimus in a synergistic manner. Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 and 2 (TSC1, TSC2). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In TSC, a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body. |
|---|---|
CAS No. |
159351-69-6 |
Molecular Formula |
C53H83NO14 |
Molecular Weight |
958.2 g/mol |
IUPAC Name |
(1R)-1,18-dihydroxy-12-[1-[4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone |
InChI |
InChI=1S/C53H83NO14/c1-32-16-12-11-13-17-33(2)44(63-8)30-40-21-19-38(7)53(62,68-40)50(59)51(60)54-23-15-14-18-41(54)52(61)67-45(35(4)28-39-20-22-43(66-25-24-55)46(29-39)64-9)31-42(56)34(3)27-37(6)48(58)49(65-10)47(57)36(5)26-32/h11-13,16-17,27,32,34-36,38-41,43-46,48-49,55,58,62H,14-15,18-26,28-31H2,1-10H3/t32?,34?,35?,36?,38?,39?,40?,41?,43?,44?,45?,46?,48?,49?,53-/m1/s1 |
InChI Key |
HKVAMNSJSFKALM-VUDSBINYSA-N |
SMILES |
CC1CCC2CC(C(=CC=CC=CC(CC(C(=O)C(C(C(=CC(C(=O)CC(OC(=O)C3CCCCN3C(=O)C(=O)C1(O2)O)C(C)CC4CCC(C(C4)OC)OCCO)C)C)O)OC)C)C)C)OC |
Isomeric SMILES |
CC1CCC2CC(C(=CC=CC=CC(CC(C(=O)C(C(C(=CC(C(=O)CC(OC(=O)C3CCCCN3C(=O)C(=O)[C@@]1(O2)O)C(C)CC4CCC(C(C4)OC)OCCO)C)C)O)OC)C)C)C)OC |
Canonical SMILES |
CC1CCC2CC(C(=CC=CC=CC(CC(C(=O)C(C(C(=CC(C(=O)CC(OC(=O)C3CCCCN3C(=O)C(=O)C1(O2)O)C(C)CC4CCC(C(C4)OC)OCCO)C)C)O)OC)C)C)C)OC |
Appearance |
White to off-white solid powder |
Key on ui application |
Everolimus is currently used as an immunosuppressant to prevent rejection of organ transplants. In a similar fashion to other mTOR inhibitors Everolimus' effect is solely on the mTORC1 protein and not on the mTORC2 protein. |
boiling_point |
998.7±75.0 °C at 760 mmHg |
melting_point |
N/A |
Other CAS No. |
159351-69-6 |
Pictograms |
Health Hazard |
Purity |
>98% (or refer to the Certificate of Analysis) |
shelf_life |
Stable under recommended storage conditions. |
solubility |
Soluble in DMSO, not in water |
storage |
−20°C |
Synonyms |
001, RAD 40-O-(2-hydroxyethyl)-rapamycin Afinitor Certican everolimus RAD 001 RAD, SDZ RAD001 SDZ RAD SDZ-RAD |
Origin of Product |
United States |
Preparation Methods
Key Synthetic Steps in Everolimus Preparation
Synthesis of the Triflate Intermediate
The preparation of this compound begins with the synthesis of a silyl-protected triflate intermediate, critical for alkylating rapamycin. A representative method involves reacting 2-([trisubstituted]silyloxy)ethanol with trifluoromethanesulfonic anhydride (Tf₂O) in the presence of a base such as 2,6-lutidine. For instance, t-butyldimethylsilyloxyethanol reacts with Tf₂O at -40°C in dichloromethane (DCM) to yield 2-(t-butyldimethylsilyloxy)ethyl triflate (Formula IVa). This intermediate is highly reactive, necessitating inert conditions and low temperatures to prevent hydrolysis.
Table 1: Reaction Conditions for Triflate Intermediate Synthesis
Alkylation of Sirolimus
The triflate intermediate reacts with sirolimus (rapamycin) to form a protected this compound derivative. This step requires a base to deprotonate sirolimus’s C-40 hydroxyl group, facilitating nucleophilic substitution. Silver acetate (AgOAc) is often added to enhance reactivity, as demonstrated in Example 1 of Patent WO2016020664A1. Sirolimus dissolved in DCM is treated with the triflate intermediate at -40°C, followed by gradual warming to 40°C. The use of 2,6-lutidine as both a base and catalyst ensures high regioselectivity, yielding 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (TBS-everolimus) with 60–85% purity.
Critical Factor : Omitting AgOAc (as in Example 2 of the same patent) reduces purity to 10–20%, underscoring the metal’s role in stabilizing the transition state.
Deprotection to Yield this compound
The final step involves cleaving the silyl protecting group using aqueous HCl in methanol. TBS-everolimus is stirred with 1N HCl at pH 1–3, resulting in quantitative deprotection to this compound. Post-reaction, the crude product is extracted with ethyl acetate and purified via preparative HPLC to achieve >99% purity.
Table 2: Deprotection Conditions and Outcomes
Optimization of Reaction Conditions
Solvent and Base Selection
Early methods used DCM for triflate synthesis but faced challenges in large-scale operations due to solvent volatility. Substituting DCM with n-heptane improved stability and facilitated easier filtration of byproducts. Similarly, replacing pyridine with 2,6-lutidine reduced side reactions, as lutidine’s steric hindrance minimizes over-alkylation.
Large-Scale Manufacturing Processes
Industrial-scale production (Example 3, WO2016020664A1) employs toluene as the solvent for sirolimus alkylation, enabling higher throughput compared to DCM. The process involves:
-
Batchwise triflate addition : Three portions of TBS-glycol-triflate are added to sirolimus at 60–65°C, achieving 60–70% conversion.
-
Solvent switching : Replacing DCM with n-heptane simplifies byproduct removal via filtration.
-
One-pot deprotection : Crude TBS-everolimus is directly treated with HCl in methanol, avoiding intermediate isolation.
This method yields 39 g of crude this compound per 30 g sirolimus, with a final purity of >99% after HPLC.
Impurity Profiling and Process Improvements
A 2021 study identified dialkylated rapamycin derivatives (PG-D, PG-E, PG-F) as major byproducts during alkylation. By adjusting the base-to-triflate ratio and reaction time, researchers redirected selectivity toward PG-E, which is hydrolyzable to this compound. This optimization increased overall yield by 10% and reduced solvent consumption by 30%.
Table 3: Impact of Process Optimization
Analytical Considerations in Synthesis
Quality control relies on HPLC and LC-MS to monitor intermediates and final product purity. For example, derivatization with N-methylaniline is used to quantify residual triflate intermediates. Regulatory submissions emphasize strict control over genotoxic impurities (e.g., triflic acid salts), requiring limits below 10 ppm .
Chemical Reactions Analysis
Types of Reactions: Everolimus undergoes various chemical reactions, including oxidation, reduction, and substitution. These reactions are essential for its metabolic processing and therapeutic action.
Common Reagents and Conditions:
Oxidation: Typically involves the use of oxidizing agents like hydrogen peroxide or potassium permanganate.
Reduction: Often carried out using reducing agents such as sodium borohydride or lithium aluminum hydride.
Substitution: Involves nucleophilic or electrophilic reagents under controlled conditions.
Major Products: The primary products formed from these reactions include various metabolites that are further processed in the body to exert their therapeutic effects .
Scientific Research Applications
Oncology Applications
Everolimus is primarily utilized in oncology for its antiproliferative properties. It has been approved by the United States Food and Drug Administration (FDA) for several cancer types, including:
- Renal Cell Carcinoma : this compound is indicated for advanced renal cell carcinoma after prior treatment with other therapies like sorafenib or sunitinib. In clinical trials, it demonstrated a median progression-free survival of 4.9 months compared to 1.9 months for placebo.
- Breast Cancer : In combination with letrozole, this compound has shown efficacy in treating hormone receptor-positive advanced breast cancer. A phase II trial revealed a notable improvement in progression-free survival.
- Gastric Cancer : A phase II study indicated that this compound could reduce the risk of disease progression in pretreated advanced gastric cancer patients, with a disease control rate significantly higher than placebo.
- Neuroendocrine Tumors : this compound is also approved for pancreatic neuroendocrine tumors, where it has shown a 65% decrease in tumor progression risk.
| Cancer Type | Indication | Median PFS (months) | Response Rate |
|---|---|---|---|
| Renal Cell Carcinoma | After prior therapy | 4.9 | 7% |
| Breast Cancer | With letrozole | Not specified | Not specified |
| Gastric Cancer | Advanced, previously treated | Not specified | 38.9% |
| Neuroendocrine Tumors | Advanced pancreatic neuroendocrine tumors | 12 | 65% decrease |
Transplantation Applications
This compound plays a crucial role in organ transplantation due to its immunosuppressive properties:
- Kidney Transplantation : It is used to prevent acute rejection in kidney transplant recipients, allowing for potential minimization or elimination of calcineurin inhibitors, which can have nephrotoxic effects.
- Other Organ Transplants : The drug has also been investigated for use in heart and liver transplants, showing promise in maintaining graft function and reducing rejection rates.
Other Therapeutic Uses
Beyond oncology and transplantation, this compound has been explored for various other conditions:
- Tuberous Sclerosis Complex : Approved for treating subependymal giant cell astrocytoma associated with tuberous sclerosis complex, this compound has shown efficacy in improving neurological function and survival rates in affected patients.
- Cardiovascular Applications : As a drug-eluting stent coating, this compound helps prevent restenosis by inhibiting smooth muscle cell proliferation.
Mechanism of Action
Everolimus exerts its effects by inhibiting the mTOR pathway, specifically targeting the mTORC1 protein complex. This inhibition disrupts cell growth, proliferation, and survival signals, leading to reduced tumor growth and immune response modulation. The molecular targets include various proteins involved in the PI3K/AKT/mTOR signaling pathway .
Comparison with Similar Compounds
Structural and Pharmacokinetic Comparisons
Table 1: Structural and Pharmacokinetic Profiles of mTOR Inhibitors
| Compound | Structural Modification | Oral Bioavailability | Half-Life (h) | Key Pharmacokinetic Advantages |
|---|---|---|---|---|
| Everolimus | 2-hydroxyethyl chain at position 40 | ~30% | 30–40 | Improved solubility vs. sirolimus |
| Sirolimus | Unmodified macrolide | ~14% | 60–70 | Long half-life, but poor oral absorption |
| Temsirolimus | Esterified C40 hydroxyl group (prodrug) | N/A (IV only) | 17–24 | Water-soluble prodrug for intravenous use |
- Key Findings: this compound’s 2-hydroxyethyl substitution increases polarity, enhancing oral bioavailability compared to sirolimus . Temsirolimus, a prodrug, is administered intravenously due to poor oral absorption .
Efficacy in Specific Cancers
Mechanistic Differences
Table 2: Proteomic and Pathway Effects
Resistance and Biomarkers
- Cross-Resistance : this compound-resistant pNET cell lines (BON-1/R, QGP-1/R) show resistance to other rapalogs (e.g., temsirolimus) .
- Biomarkers: In breast cancer, PIK3CA mutations (e.g., H1047R) correlate with this compound efficacy (HR = 0.37 for PFS) . No consistent association between PI3K/AKT/mTOR pathway activity and response in biliary tract cancer .
Cost-Effectiveness
Table 3: Cost per Additional Month of Survival in RCC
| Treatment | Additional Cost/Month of OS vs. This compound |
|---|---|
| Cabozantinib | $48,773 |
| Nivolumab | $24,214 |
| Axitinib | Similar OS, lower cost |
- This compound remains cost-effective compared to axitinib but is less economical than nivolumab .
Biological Activity
Pharmacodynamics
The pharmacodynamic profile of this compound includes its effects on various biomarkers associated with mTOR signaling. A comprehensive study indicated that this compound effectively inhibited phosphorylation of ribosomal protein S6, a common marker for mTORC1 activity. The study also revealed that daily dosing at 10 mg provided more robust and prolonged inhibition compared to weekly dosing schedules.
Key Pharmacodynamic Findings
| Parameter | Daily Dosing (10 mg) | Weekly Dosing (50 mg) |
|---|---|---|
| S6 Phosphorylation Inhibition | Almost complete | Moderate |
| Proliferation Reduction | Significant | Moderate |
| Hyperphosphorylation of Akt | Observed in ~50% samples | Not maintained |
Clinical Efficacy
This compound has been evaluated in numerous clinical trials demonstrating its efficacy across various cancer types. Notably, it has shown significant activity in patients with renal cell carcinoma who are refractory to other therapies.
Case Studies
- Renal Cell Carcinoma : In a pivotal trial involving 410 patients with advanced renal cell carcinoma, this compound demonstrated a median progression-free survival (PFS) of 4.9 months compared to 1.9 months for placebo.
- Neuroendocrine Tumors : A study involving patients with advanced neuroendocrine tumors showed an overall response rate (ORR) of 32% when treated with this compound, highlighting its potential in this indication.
Safety Profile
While this compound is generally well-tolerated, it is associated with several adverse effects:
Table of Adverse Effects
| Adverse Effect | Incidence (%) |
|---|---|
| Stomatitis | 40 |
| Infections | 30 |
| Fatigue | 25 |
| Renal Failure | 10 |
Q & A
Basic Research Questions
Q. What are the key considerations for designing phase III clinical trials evaluating everolimus in hormone receptor-positive advanced breast cancer?
- Trials should randomize patients with prior nonsteroidal aromatase inhibitor (NSAI) resistance to this compound + exemestane vs. placebo + exemestane, using progression-free survival (PFS) as the primary endpoint. Stratification factors (e.g., visceral metastases, prior chemotherapy) ensure balanced cohorts. Interim analyses by independent committees are critical for early efficacy/safety assessments . Secondary endpoints include overall survival (OS) and objective response rates.
Q. How should researchers address adverse events (AEs) like stomatitis and hyperglycemia in this compound trials?
- Proactively monitor AEs using CTCAE criteria. Grade 3/4 stomatitis (8% incidence) may require dose reductions or topical therapies, while hyperglycemia (4%) necessitates glucose monitoring and antihyperglycemic agents. Preemptive patient education and AE management protocols improve trial adherence .
Q. What statistical methods are appropriate for analyzing PFS in this compound trials?
Advanced Research Questions
Q. How do PI3K/AKT/mTOR pathway alterations influence this compound efficacy across cancer types?
- In HER2+ breast cancer, PIK3CA mutations or PTEN loss correlate with improved PFS (HR 0.67 for hyperactive PI3K pathway). Conversely, wild-type PI3K tumors derive minimal benefit. Use next-generation sequencing (NGS) and immunohistochemistry to stratify patients by biomarker status in trials .
Q. What methodologies resolve contradictions in this compound efficacy between renal cell carcinoma (RCC) and pancreatic neuroendocrine tumors (pNET)?
- In pNET, this compound improves median PFS by 6.4 months (HR 0.35), whereas in RCC, nivolumab outperforms this compound in OS (25.0 vs. 19.6 months). Contextual factors like tumor microenvironment and prior therapies (e.g., antiangiogenic agents in RCC) require subgroup analyses and translational studies .
Q. How can pharmacokinetic (PK) data optimize this compound dosing in heterogeneous populations?
- Phase I PK studies show dose-proportional AUC but saturable Cmax beyond 20 mg/week. A 10 mg/day regimen achieves steady-state concentrations with manageable toxicity. Model-informed drug development (MIDD) tools, such as pharmacodynamic (PD) biomarkers (e.g., S6K1 inhibition), guide dose adjustments in organ dysfunction .
Q. What strategies validate exploratory biomarkers (e.g., chromogranin A) for this compound response prediction?
Q. Methodological Frameworks
Q. How to structure a PICOT-compliant research question for this compound trials?
- P opulation: Postmenopausal women with HR+/HER2- advanced breast cancer; I ntervention: this compound + exemestane; C omparison: Placebo + exemestane; O utcome: PFS; T ime: 12-month follow-up. This framework ensures clarity and feasibility .
Q. What tools analyze this compound-induced transcriptomic changes in tumor samples?
- RNA-seq paired with pathway enrichment analysis (e.g., Gene Set Enrichment Analysis) identifies mTORC1-dependent gene signatures. Single-cell sequencing can dissect intratumoral heterogeneity and resistance mechanisms .
Q. How to design a crossover-adjusted OS analysis in this compound trials?
Q. Data Interpretation & Reporting
Q. Why do central vs. local PFS assessments differ in this compound trials?
Q. How to reconcile negative OS results despite significant PFS benefits?
Q. Emerging Research Directions
Q. What trial designs evaluate this compound in CDK4/6 inhibitor-resistant HR+ breast cancer?
Retrosynthesis Analysis
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Strategy Settings
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| 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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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.
