UNC8209
UNC8209 is a selective PROTAC-based TANK-binding kinase 1 (TBK1) degrader. UNC8209 recruits cereblon (CRBN) to mediate ubiquitin-proteasome pathway-dependent TBK1 degradation and reduces AAK1, GAK, and AURKA abundance. UNC8209 suppresses tumor cell proliferation, impairs in vivo tumor growth, inhibits colony and clonogenic growth and enhances tumor cell sensitivity to TNFα or IFN-γ. UNC8209 modulates cell cycle and induces mild apoptosis. UNC8209 can be used for the research of clear cell renal cell carcinoma, non-small cell lung cancer, pancreatic ductal adenocarcinoma.
(Pink: TBK1 ligand (HY-183099); Blue: Cereblon ligand (HY-10984); Black: linker).
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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。
- 分子式: C45H58BrN7O12
- 分子量:968.89
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保管条件:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
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
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生物活性
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TBK1 |
UNC8209 (0.01-3 μM; 4-48 h) potently and selectively degrades TBK1 in UMRC6, A498, 769-P, UMRC2, and 786-O ccRCC cells, and has minimal impact on IKKε protein levels at standard concentrations[1].
UNC8209 (1 μM; 8-24 h) mediates TBK1 degradation in UMRC6 and A498 ccRCC cells through a CRBN-dependent, proteasome-dependent pathway[1].
UNC8209 (1 μM; 6 h) treatment of UMRC2 ccRCC cells leads to selective downregulation of TBK1 and secondary downregulation of AAK1, GAK, AURKA, and FLJ45252, with no significant effect on common TBK1 inhibitor off-target kinases[1].
UNC8209 (1 μM; 24 h) treatment of UMRC6 and A498 ccRCC cells leads to reduced levels of AAK1, GAK, and AURKA, as a secondary consequence of TBK1 degradation[1].
UNC8209 (0.1-4 μM; 7-14 days) potently inhibits proliferation of VHL-deficient ccRCC cells (769-P, A498, UMRC6, UMRC2, RCC4, 786-O, Caki-1) and TBK1-active normal kidney epithelial HK-2 cells, with limited activity in low-TBK1-activity VHL-proficient ACHN and HKC cells[1].
UNC8209 (1 μM; 4-6 weeks) inhibits anchorage-independent growth of VHL-deficient ccRCC cells (769-P, A498, UMRC6, UMRC2, 786-O, Caki-1) in soft agar, with limited activity in ACHN and HKC cells[1].
UNC8209 (0.01-4 μM; 24 h, continuous incubation) potently degrades TBK1 and inhibits proliferation of TBK1-active NSCLC A549 cells and PDAC PANC1 cells[1].
UNC8209 (1 μM; continuous incubation) synergizes with TNF-α (50 ng/mL) and IFN-γ (10 ng/mL) to suppress proliferation of NSCLC A549 cells and PDAC PANC1 cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:UMRC6, A498, 769-P, UMRC2, 786-O (human clear cell renal cell carcinoma cell lines)
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Concentration:0.01 μM; 0.03 μM; 0.1 μM; 0.3 μM; 1 μM; 3 μM
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Incubation Time:24 h
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Result:Induced potent, sustained TBK1 degradation with minimal effect on IKKε at standard concentrations.
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Cell Line:UMRC6, A498, 769-P, UMRC2, 786-O (human clear cell renal cell carcinoma cell lines)
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Concentration:0.01 μM; 0.03 μM; 0.1 μM; 0.3 μM; 1 μM; 3 μM
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Incubation Time:4 h, 24 h, 48 h
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Result:Detected TBK1 degradation as early as 4 h post-treatment and persisted for up to 48 h in UMRC6 cells.
Achieved a half-maximal degradation concentration (DC50) of 80 nM and maximal degradation (DMax) of 94% after 24 h in A498 cells.
Achieved a DC50 of 23 nM with a DMax of 94% after 24 h in 769-P cells.
Observed a mild "hook effect" at concentrations above 1 μM in A498 and 769-P cells, with reduced degradation at higher doses.
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Cell Line:UMRC6, A498 (human clear cell renal cell carcinoma cell lines)
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Concentration:1 μM; 1 μM plus MG132 (10 μM)
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Incubation Time:8 h; 24 h
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Result:Completely blocked UNC8209-induced TBK1 degradation in UMRC6 cells when treated with MG132.
Abrogated TBK1 degradation in A498 cells after genetic depletion of CRBN using CRISPR/Cas9, phenocopying the effect of MG132.
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Cell Line:UMRC6, A498 (human clear cell renal cell carcinoma cell lines)
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Concentration:1 μM
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Incubation Time:24 h
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Result:Reduced the abundance of AAK1, GAK, and AURKA proteins in both UMRC6 and A498 cells.
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Cell Line:A549, PABC1
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Concentration:0.01 μM; 0.1 μM; 0.5 μM; 1 μM; 2 μM
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Incubation Time:24 h
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Result:Degraded TBK1 and inhibited proliferation of TBK1-active NSCLC.
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Cell Line:A549 (human non-small cell lung cancer cell line); PANC1 (human pancreatic ductal adenocarcinoma cell line)
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Concentration:1 μM; 1 μM plus 50 ng/mL TNF-α; 1 μM plus 10 ng/mL IFN-γ
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Incubation Time:continuous incubation
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Result:Produced a synergistic effect when co-treated with TNF-α or IFN-γ, significantly enhancing suppression of tumor cell growth compared to single-agent treatment.
Produced only modest effects when treated with cytokine alone.
UNC8209 (10-40 mg/kg; i.p.; single dose) distributes to both plasma and subcutaneous UMRC2 ccRCC xenograft tumors in NSG mice after a single intraperitoneal injection, with measurable target engagement via TBK1 degradation[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:NOD SCID Gamma (NSG) (6-week-old, male to female ratio 2:1, subcutaneous xenograft with A498 cells)[1]
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Dosage:10 mg/kg; 20 mg/kg
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Administration:i.p.; daily; two and a half weeks
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Result:Significantly suppressed tumor growth compared to vehicle controls, with reduced tumor volume and tumor weight at 10 mg/kg.
Caused no significant mouse body weight loss, no significant differences in liver, kidney, heart, or spleen weights, and no overt tissue damage on histopathological analysis at 10 mg/kg.
Resulted in greater suppression of tumor volume and weight compared to vehicle and the 10 mg/kg group at 20 mg/kg.
Caused mild mouse body weight loss after two weeks of treatment, and prevented mice from surviving to the planned experimental endpoint at 20 mg/kg.
Substantially downregulated TBK1 protein expression in tumors from both treatment groups, with stronger degradation in the 20 mg/kg group.
Induced concurrent degradation of IKKε in the 20 mg/kg group.
Downregulated AAK1, GAK, and AURKA protein levels in tumors from treated mice.
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Animal Model:NOD SCID Gamma (NSG) (bearing established UMRC2 xenografts with tumor diameter ~10 mm)[1]
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Dosage:10 mg/kg; 20 mg/kg; 40 mg/kg
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Administration:i.p.; single dose
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Result:Was detectable in both plasma and tumor tissues across all treatment groups, with dose-dependent increases in compound levels (non-linear, suggesting potential saturation of absorption or tissue distribution).
Reduced TBK1 protein levels in tumors from treated mice, with a more pronounced effect at lower doses.
化学情報
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分子量 968.89
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分子式 C45H58BrN7O12
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SMILES
CN(C(C1CCC1)=O)CCCNC2=NC(NC3=CC=C(C=C3)OCCOCCOCCOCCOCCOCCCOC4=CC=CC5=C4C(N(C5=O)C6CCC(NC6=O)=O)=O)=NC=C2Br
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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)
UNC8209 関連分類
HY-183098 関連分類
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