CB-5083 |
Katalog-Nr.GC16351
One-Click Copy Product Info
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CB-5083 ist ein erstklassiger, potenter, selektiver und oral bioverfÜgbarer Inhibitor der p97 AAA ATPase/VCP. CB-5083 hemmt selektiv p97 Über seine D2-Stelle mit einem IC50 von 11 nM。
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1542705-92-9
Sample solution is provided at 25 µL, 10mM.
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CB-5083 is a highly selective and orally bioavailable AAA-ATPase p97 inhibitor with an IC50 value of 11nM[1]. P97 is an enzyme involved in clearing misfolded proteins. CB-5083 binds to and inhibits p97 activity, leading to accumulation of ubiquitinated proteins, inducing prototoxic stress and activating apoptosis to exert anti-tumor activity (Fig 1)[2]. CB-5083 is commonly used as an anti-cancer agent in research on multiple myeloma and solid tumor models[3,4].
Fig 1. Mechanism of action of CB-5083[5,6]. CB-5083 specifically targets the Valosin-Containing Protein (VCP) p97. By inhibiting the ATPase activity of p97, CB-5083 blocks the ubiquitin-proteasome system and endoplasmic reticulum-associated protein degradation (ERAD), leading to the accumulation of misfolded and damaged proteins. This subsequently triggers the unfolded protein response and prototoxic stress, ultimately resulting in cancer cell death.
In vitro, treatment of myeloma RPMI8226 cells with CB-5083 (0.3125-20μM) for 8h induced expression of unfolded protein response (UPR) markers sXBP1 and BiP, and accumulation of K48 polyubiquitinated proteins[5]. Treatment of human osteosarcoma SJSA-1 and U2OS cells with CB-5083 (0.5, 1 μM) for 48h induced G1 phase cell cycle arrest and promoted apoptosis[7]. Treatment of THP-1 and MV4-11 cells with CB-5083 (200nM) for 6h altered the ubiquitin-modified proteome, including ubiquitination levels of Valosin-containing protein (VCP) itself, proteasome components, autophagy-related proteins, and DNA damage response factors[8].
In vivo, oral administration of CB-5083 (60mg/kg) to severe combined immunodeficiency disease (SCID) beige mice bearing RPMI8226 xenografts resulted in plasma levels of CB-5083 within 2-20μM over 24h, sustained significant K48 polyubiquitinated protein accumulation, activated UPR, and increased CHOP protein expression by 2.7-fold compared to baseline[5]. Oral gavage of CB-5083 (15mg/kg) to 2-month-old VCPR155H/R155H homozygous mice for 5 months was well tolerated, with steady body weight gain and normal organ weights, did not increase liver enzymes (such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), and significantly reduced AST levels[9].
References:
[1] ZHOU H J, WANG J, YAO B, et al. Discovery of a first-in-class, potent, selective, and orally bioavailable inhibitor of the p97 AAA ATPase (CB-5083)[J]. 2015.
[2] ANDERSON D J, LE MOIGNE R, DJAKOVIC S, et al. Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis[J]. Cancer Cell, 2015, 28(5): 653-665.
[3] LEBLANC A K, MAZCKO C N, FAN T M, et al. Comparative oncology assessment of a novel inhibitor of valosin-containing protein in tumor-bearing dogs[J]. Molecular Cancer Therapeutics, 2022, 21(10): 1510-1523.
[4] WANG F, LI S, HOUERBI N, et al. Temporal proteomics reveal specific cell cycle oncoprotein downregulation by p97/VCP inhibition[J]. Cell Chemical Biology, 2022, 29(3): 517-529.
[5] LE MOIGNE R, AFTAB B T, DJAKOVIC S, et al. The p97 inhibitor CB-5083 is a unique disrupter of protein homeostasis in models of multiple myeloma[J]. Molecular Cancer Therapeutics, 2017, 16(11): 2375-2386.
[6] CB-5083 is a selective and orally bioavailable p97 inhibitor[EB/OL]. (2020-12-17) [2025-10-02]. https://www.immune-system-research.com/2020/12/17/cb-5083-is-a-selective-and-orally-bioavailable-p97-inhibitor/.
[7] ZHAO Z, WU M, ZHANG X, et al. CB-5083, an inhibitor of P97, suppresses osteosarcoma growth and stem cell properties by altering protein homeostasis[J]. American Journal of Translational Research, 2020, 12(6): 2956.
[8] SZCZĘŚNIAK P P, HEIDELBERGER J B, SERVE H, et al. VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells[J]. PLoS One, 2022, 17(4): e0266478.
[9] CHENG C, WEISS L, LEINONEN H, et al. VCP/p97 inhibitor CB-5083 modulates muscle pathology in a mouse model of VCP inclusion body myopathy[J]. Journal of Translational Medicine, 2022, 20(1): 21.
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Kinase experiment [1]: |
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Preparation Method
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Compounds were diluted in DMSO with a 3-fold 10-point serial dilution starting at 10μM. The assay was done in a 384-well plate with each row as a single dilution series with duplicate of each compound concentration point. In 5μL total volume, 20nM p97 hexameric enzyme and 20μM ATP were added to start the reaction. The plate was sealed and incubated at 37℃ for 15min after mixing thoroughly in an orbital shaker. Compound dilution, ATP and enzymes addition were conducted with automated liquid handling, then ADP Glo reagents 1 and 2 were added. The luminescence was measured by Envision plate reader as the end point of the reaction. The IC50 of CB-5083 was derived by fitting the luminescence values to a four-parameter sigmoidal curve. |
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Reaction Conditions
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3-fold 10-point serial dilution starting at 10μM; 15min |
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Applications
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CB-5083 selectively inhibits p97 through its D2 site with the IC50 of 11nM. |
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Cell experiment [2]: |
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Cell lines |
SJSA-1 and U2OS cells |
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Preparation Method |
The SJSA-1 and U2OS cells were treated with 0, 0.5 and 1μM CB-5083 for 48h and then collected. Cell cycle assays were performed using propidium iodide (PI) staining and flow cytometry, and cell apoptosis was detected by annexin V/PI staining and flow cytometry. |
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Reaction Conditions |
0, 0.5, and 1μM; 48h |
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Applications |
The treatment increased the percentages of cells at the G0/G1 phase, decreased the percentages of cells at the S phase, and did not affect the percentages of cells at the G2/M phase. CB-5083 induced G1 cell cycle arrest and apoptosis in osteosarcoma cells. |
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Animal experiment [3]: |
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Animal models |
SCID beige mice bearing RPMI8226 tumors |
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Preparation Method |
SCID beige mice bearing RPMI8226 tumors received a single oral dose of CB-5083 at 60mg/kg. Tumors were collected at 1, 6, and 24h postdose, and tumor lysates were subjected to MSD analysis for K48 ubiquitin. |
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Dosage form |
60mg/kg; p.o. |
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Applications |
In RPMI8226 xenografts, a single dose of CB-5083 led to plasma levels of CB-5083 that ranged from 2 to 20μM over a period of 24h, sufficient to maintain significant K48 polyubiquitin accumulation. This dose was sufficient to activate the UPR, and CHOP protein expression increased up to 2.7-fold compared with baseline levels. |
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References: [1] ZHOU H J, WANG J, YAO B, et al. Discovery of a first-in-class, potent, selective, and orally bioavailable inhibitor of the p97 AAA ATPase (CB-5083) [J]. 2015. [2] ZHAO Z, WU M, ZHANG X, et al. CB-5083, an inhibitor of P97, suppresses osteosarcoma growth and stem cell properties by altering protein homeostasis[J]. American Journal of Translational Research, 2020, 12(6): 2956. [3] LE MOIGNE R, AFTAB B T, DJAKOVIC S, et al. The p97 inhibitor CB-5083 is a unique disrupter of protein homeostasis in models of multiple myeloma[J]. Molecular Cancer Therapeutics, 2017, 16(11): 2375-2386. |
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| Cas No. | 1542705-92-9 | SDF | |
| Chemical Name | (E)-1-(4-(benzylimino)-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carbimidic acid | ||
| Canonical SMILES | CC1=CC2=C(C(O)=N)C=CC=C2N1C3=NC4=C(/C(N3)=N\CC5=CC=CC=C5)COCC4 | ||
| Formula | C24H23N5O2 | M.Wt | 413.47 |
| Löslichkeit | ≥ 20.65mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4186 mL | 12.0928 mL | 24.1856 mL |
| 5 mM | 483.7 μL | 2.4186 mL | 4.8371 mL |
| 10 mM | 241.9 μL | 1.2093 mL | 2.4186 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
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Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )
Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL saline, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >99.50% Appearance: A solid
- COA (Certificate of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 2 reference(s) in Google Scholar.)