GDCNF-11
GDCNF-11 is a type of HSP90 interaction-mediated protein degradation chimera (HIM-PROTAC) degrader that targets and degrades GPX4, with a DC50 of 0.08 μM. GDCNF-11 mediates the ubiquitination and proteasome-dependent degradation of GPX4 by recruiting GPX4 to form a ternary complex with HSP90, increases intracellular lipid peroxides and ROS, and ultimately triggers Ferroptosis. GDCNF-11 inhibits tumor growth in mouse models, downregulates GPX4 protein in xenograft tumors, and upregulates the lipid peroxidation marker. GDCNF-11 can be used for the research of fibrosarcoma.
(Pink: GPX4 ligand (HY-153748); Blue: HSP90 ligand (HY-10212); Black: linker (HY-159772)).
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研究用途以外に使用した場合、当社は一切の責任を負いかねます。
- CAS 番号: 2991588-80-6
- 分子式: C48H53Cl2N13O5S
- 分子量:994.99
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保管条件:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Tel: 609-228-6898 E-mail: [email protected] [email protected]
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生物活性
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化学情報
- 純度とドキュメンテーション
- 参考文献
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生物活性
製品説明
IC50 & Target
[1]|
GPX4 0.08 μM (DC50) |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| HT-1080 | IC50 |
0.74 μM
Compound: GDCNF-11
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Cytotoxicity against human HT-1080 cells incubated for 48 hrs by CCK-8 assay
Cytotoxicity against human HT-1080 cells incubated for 48 hrs by CCK-8 assay
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[PMID: 39230973] |
| HT-1080 | IC50 |
35.5 μM
Compound: GDCNF-11
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Cytotoxicity against human HT-1080 cells incubated for 48 hrs in presence of Fer-1 by CCK-8 assay
Cytotoxicity against human HT-1080 cells incubated for 48 hrs in presence of Fer-1 by CCK-8 assay
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[PMID: 39230973] |
体外実験
GDCNF-11 (0.03-3 μM; 2-24 h, 24 h treatment followed by 0-24 h washout) potently degrades GPX4 in HT-1080 cells with a DC50 of 0.08 μM, following a time-dependent pattern with transient early upregulation and sustained post-washout activity for 12 h[1].
GDCNF-11 (0.1-1 μM; 24 h) does not alter GPX4 mRNA expression in HT-1080 cells, indicating it acts by degrading GPX4 protein rather than modulating transcription[1].
GDCNF-11 binds to recombinant human HSP90α with high affinity, with a Kd value of 0.19 μM; it inhibits the growth of HT-1080 cells, with an IC50 of 0.74 μM; and its cytotoxicity is mainly mediated by ferroptosis[1].
GDCNF-11 (0.3-1 μM; 24 h, 2 h pretreatment) induces proteasome-dependent GPX4 degradation in HT-1080 cells via HSP90 (both α and β isoforms) recruitment, ternary complex formation, and ubiquitination mediated by cullin E3 ligases including CUL5 and CHIP[1].
GDCNF-11 forms a stable ternary complex with HSP90 and GPX4 via conserved ligand-protein interactions and additional inter-protein contacts, supporting its mechanism of action as an HIM-PROTAC[1].
GDCNF-11 (1 μM; 24 h) exhibits high selectivity for GPX4 degradation in HT-1080 cells, with only a small number of additional proteins significantly altered, including upregulated HMOX1[1].
GDCNF-11 (varied; 12 h) dose-dependently increases intracellular lipid peroxidation in HT-1080 cells, an effect that is abrogated by ferroptosis inhibitor Fer-1, consistent with ferroptosis induction[1].
GDCNF-11 (1 μM; 24 h) induces a significant increase in intracellular ROS and Fe2+ levels in HT-1080 cells, consistent with ferroptosis activation[1].
GDCNF-11 (1 μM; 24 h) induces ferroptosis-specific mitochondrial morphological changes and autophagosome-like structures in HT-1080 cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:HT-1080 fibrosarcoma cells
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Concentration:0.03, 0.06, 0.1, 0.3, 0.6, 0.8, 1 μM (dose-dependent assays)
1 μM (time-course and washout assays) -
Incubation Time:24 h (dose-dependent assays)
2, 4, 6, 12, 24 h (time-course and washout assays) -
Result:Reduced GPX4 protein levels in a dose-dependent manner, with a GPX4 degradation DC50 of 0.08 μM after 24 h treatment.
Observed a hook effect, with decreased degradation efficacy at 3 μM.
Began to decrease GPX4 protein levels after 12 h of treatment with 1 μM, reaching near-complete depletion at 24 h; noted a transient upregulation of GPX4 at 4 h post-treatment.
Induced sustained GPX4 degradation for 12 h after washout of 1 μM.
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Cell Line:HT-1080 fibrosarcoma cells
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Concentration:0.1, 0.3, 1 μM
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Incubation Time:24 h
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Result:Did not significantly affect GPX4 mRNA levels at any of the tested concentrations.
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Cell Line:HT-1080 fibrosarcoma cells
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Concentration:0.3, 1 μM
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Incubation Time:24 h
2 h pretreatment -
Result:Had its induced GPX4 degradation completely abrogated by MG132 (HY-13259) pretreatment, confirming proteasome-dependent degradation.
Had its induced GPX4 depletion rescued by pretreatment with ML162 (HY-100002) or BIIB021 (HY-10212), demonstrating binding to GPX4 and HSP90 at their respective ligand sites.
Had its induced GPX4 degradation abrogated by HSP90 siRNA knockdown; selective inhibition of either HSP90α or HSP90β reduced degradation efficacy, with combined inhibition further diminishing activity, showing both isoforms contribute to degradation.
Had its induced GPX4 degradation rescued by MLN4924 (HY-70062) pretreatment, confirming cullin E3 ligase involvement.
Had its induced GPX4 degradation reduced by CUL5 or CHIP siRNA knockdown, indicating these E3 ligases mediate the process.
Increased GPX4 ubiquitination levels and promoted co-immunoprecipitation of HSP90 and GPX4, confirming ternary complex formation and ubiquitination-dependent degradation.
Parmacokinetics
| Species | Dose | Route | T1/2 | Tmax | Cmax | MRT0-inf | AUC0-t | AUC0-inf |
|---|---|---|---|---|---|---|---|---|
| Mice[1] | 25 mg/kg | i.p. | 5.0 h | 2 h | 53.1 ng/mL | 6.2 h | 334 ng·h/mL | 346 ng·h/mL |
体内実験
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:HT-1080 tumor-bearing nude mice (5 weeks old, 18-20 g)[1]
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Dosage:25 mg/kg; 50 mg/kg; 100 mg/kg
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Administration:i.p.; daily; single injection
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Result:Suppressed HT-1080 xenograft growth dose-dependently with stronger antitumor activity than 25 mg/kg ML162 and 25 mg/kg BIIB021.
Downregulated tumor GPX4 and upregulated 4-hydroxynonenal at 12, 24 and 36 h after single 50 mg/kg or 100 mg/kg injection; 50 mg/kg administration only caused mild weight loss and no pathological injury in major organs verified by H&E staining.
Exerted full biosafety with zero mouse deaths at 50 mg/kg, whereas the combination of ML162 and BIIB021 resulted in four mouse deaths by day 18.
化学情報
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CAS 番号 2991588-80-6
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分子量 994.99
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分子式 C48H53Cl2N13O5S
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SMILES
NC1=NC(NCCC2CCN(CC2)C(CN3N=NC(COC4=C(C=C(C=C4)N(C(CCl)=O)C(C(NCCC5=CC=CC=C5)=O)C6=CC=CS6)Cl)=C3)=O)=C(C7=N1)N=CN7CC8=C(C(OC)=C(C=N8)C)C
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輸送条件
Room temperature in continental US; may vary elsewhere.
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保管条件
Please store the product under the recommended conditions in the Certificate of Analysis.
純度とドキュメンテーション
参考文献
Calculators
濃度 (開始) × 体積 (開始) = 濃度 (終了) × 体積 (終了)
GDCNF-11 関連分類
HY-169133 関連分類
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