CB-5339 |
| Katalog-Nr.GC20117 |
CB-5339 ist ein potenter und selektiver Wirkstoff der zweiten Generation, der oral bioverfügbar ist und ATP-kompetitiv wirkt. Es handelt sich um einen kleinen Molekülinhibitor von Valosin-haltigem Protein (VCP)/p97 [1,2].
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1863952-15-1
Sample solution is provided at 25 µL, 10mM.
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CB-5339 is a second generation, potent and selective, orally bioavailable, ATP-competitive, small molecule inhibitor of valosin containing protein (VCP)/p97 [1,2]. CB-5339 is an ATP-competitive, small molecule inhibitor of p97 with IC50 of 53 nM [3].
CB-5339 effectively effect on a panel of 16 primary AML patient samples harboring diverse genetic backgrounds. The median IC50 value was 375 nM among these samples [1]. CB-5339 (200 to 1000 nM for 48 hours) induces in vitro loss of viability in AML cell lines (OCI-AML3, MOLM13, SET2 and HEL92.1.7 cells), as well as in fresh, patient-derived (PD) AML cells, including those with TP53 mutations and/or TP53 allelic loss, or with 3q26 (MECOM locus) lesions and EVI1 overexpression [2]. CB-5339 induced accumulation of polyubiquitylated proteins, retention of ERAD substrates, and lethal ER stress in cancer cells mediated by CHOP, DR5 and NOXA [2].
CB-5339 has higher bioavailability than CB-5083 [1]. Treatment with CB-5339 (90 mg/kg) reduced invasion of myeloid leukemia and prolonged survival in an MLL-AF9-driven PDX AML mouse model [1]. In a tail-vein infused, luciferase transduced, aggressive xenograft model of MOLM13 cells, after AML engraftment, co-treatment for 3 weeks with CB-5339 (50 mg/kg/day, PO) and either venetoclax (30 mg/kg/day, PO) or OTX015 (30 mg/kg/day, PO), as compared to treatment with vehicle or each drug alone, significantly reduced the AML burden and improved median and overall survival of the NSG mice, without inducing significant toxicity [2].
References:
[1]. B Roux B, Vaganay C, Vargas J D, et al. Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor[J]. Science translational medicine, 2021, 13(587): eabg1168.
[2]. Fiskus W C, Das K, Mill C P, et al. Efficacy of Vcp/p97 Inhibitor, CB-5339, Alone and in Combinations Against High-Risk AML, Including Those with Genetic Lesion in TP53[J]. Blood, 2022, 140(Supplement 1): 8807-8808.
[3]. Wang X, Wen T, Miao H, et al. Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of colorectal cancer[J]. Bioorganic & Medicinal Chemistry, 2022, 74: 117050.
| Cell experiment [1]: | |
|
Cell lines |
16 primary patient acute myeloid leukemia (AML) cells |
|
Preparation Method |
Growth inhibition of 16 primary patient AML samples treated with increasing concentrations of CB-5339 for 6 days. |
|
Reaction Conditions |
0-1 µM, 6 days |
|
Applications |
The median IC50 value was 375 nM among these samples, thus supporting the translational potential of CB-5339. |
| Animal experiment [2]: | |
|
Animal models |
8-week-old male NSG mice, 6-week-old C57BL/6 male mice, or 6-week-old male and female NSGS or NOG-EXL mice |
|
Preparation Method |
1x106 MV4-11-luc cells, 100,000 or 200,000 MLLAF9-DsRed-L-GMP cells, or 500,000 patient derived primary AML cells were injected via tail vein into 8-week-old male NSG mice, 6-week-old C57BL/6 male mice, or 6-week-old male and female NSGS or NOG-EXL mice respectively. CB-5339 was delivered through oral gavage at the indicated doses. Doxorubicin and cytarabine were used intraperitoneally, respectively at 0.5 mg/kg for 3 days and 75 mg/kg for 5 days. Mice were imaged at the indicated time points on an IVIS Spectrum to assess bioluminescence. |
|
Dosage form |
Oral, CB-5339 at 50 mg/kg for 4 days |
|
Applications |
Treatment with CB-5339 reduced invasion of myeloid leukemia and prolonged survival. |
|
References: [1]: Roux B, Vaganay C, Vargas J D, et al. Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor[J]. Science translational medicine, 2021, 13(587): eabg1168. |
|
| Cas No. | 1863952-15-1 | SDF | |
| Chemical Name | 1-(4-(benzylamino)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carboxamide | ||
| Canonical SMILES | O=C(N)C1=CC=CC2=C1C=C(C)N2C3=NC(NCC4=CC=CC=C4)=C(CCCN5)C5=N3 | ||
| Formula | C24H24N6O | M.Wt | 412.49 |
| Löslichkeit | DMSO : 41.67 mg/mL | 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 | 2.4243 mL | 12.1215 mL | 24.243 mL |
| 5 mM | 0.4849 mL | 2.4243 mL | 4.8486 mL |
| 10 mM | 0.2424 mL | 1.2122 mL | 2.4243 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
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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 ddH2O, 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: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 15 reference(s) in Google Scholar.)
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