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Purity: ≥98%
CPI-455 is a novel, potent and specific inhibitor of the KDM5 demethylase which catalyzes the demethylation of histone H3 on lysine 4 (H3K4) and is required for the survival of drug-tolerant persister cancer cells (DTPs). CPI-455 elevates the global levels of H3K4 trimethylation (H3K4me3) and decreases the number of DTPs in multiple cancer cell line models treated with standard chemotherapy or targeted agents. CPI-455 has improved potency against KDM5A while demonstrating ~200-fold selectivity for KDM5A over KDM4C. CPI-455 inhibits KDM5A, KDM5B and KDM5C to similar extents but showed substantially weaker potency toward KDM4C and KDM7B (~200- and 770-fold, respectively) and no measurable inhibition of KDM2B, KDM3B or KDM6A. CPI-455-mediated KDM5 inhibition results in a dose-dependent increase in global H3K4me3 in HeLa cells.
ln Vitro |
Several cancer cell line models treated with normal chemotherapy or targeted medicines show that CPI-455 reduces the amount of DTPs, raises overall levels of H3K4 trimethylation (H3K4me3), and facilitates KDM5 inhibition [1]. High affinity for the target KDM5 protein is possessed by CPI-455. Within 24 hours of exposure to either of the two active drugs, CPI-455 and CPI-766, a dose-dependent elevation in H3K4me3 was seen. Three luminal breast cancer cell lines, MCF-7, T-47, and EFM-19, had computed IC50 values of 35.4, 26.19, and 16.13 μM for the KDM5 inhibitor CPI0455, respectively [2].
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ln Vivo |
Mice treated with CPI-455 (50/70 mg/kg, intraperitoneal injection, daily) for dual blockade of B7-H4 and KDM5B developed protective immunity [2].
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Animal Protocol |
Animal/Disease Models: Sixweeks old male C57BL/6 mice (One- to 2-mm fragments of P. gingivalis–positive PDXs were implanted subcutaneously (sc) into the flank region of humanized mice.)
Doses: 50 mg/kg or 70 mg/ kg (combined with anti–B7-H4). Route of Administration: IP, daily, 14-28 days. Experimental Results: Histopathology analysis revealed no inflammation in either group at 2 weeks in response to the primary infection. However, at 8 weeks after inoculation, mice receiving monotherapy demonstrated mild inflammation, whereas the combined treatment presented with heavy to severe inflammation, which persisted at 12 and 16 weeks after challenge. Treatment with CPI-455 to selectively target H3K4-specific JmjC demethylases increased CXCL11, CXCL9, and CXCL10 following infection , with maximum levels observed 48 hrs (hours) after infection. |
References |
[1]. Vinogradova M, et al. An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells. Nat Chem Biol. 2016 Jul;12(7):531-8.
[2]. Benjamin R. Leadem. NOVEL HISTONE DEMETHYLASE INHIBITORS SYNERGISTICALLY [3]. Xiang Yuan, et al. Blockade of Immune-Checkpoint B7-H4 and Lysine Demethylase 5B in Esophageal Squamous Cell Carcinoma Confers Protective Immunity against P. gingivalis Infection. Cancer Immunol Res. 2019 Sep;7(9):1440-1456. |
Molecular Formula |
C16H15CLN4O
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Molecular Weight |
314.77
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CAS # |
1628208-23-0
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Related CAS # |
CPI-455 hydrochloride;2095432-28-1
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Appearance |
Typically exists as solids (or liquids in special cases) at room temperature
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SMILES |
N#CC1=C(NC(C2=CC=CC=C2)=C(C(C)C)C3=O)N3N=C1
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Synonyms |
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80: Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 :Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400  (Please use freshly prepared in vivo formulations for optimal results.) |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 3.1769 mL | 15.8846 mL | 31.7692 mL | |
5 mM | 0.6354 mL | 3.1769 mL | 6.3538 mL | |
10 mM | 0.3177 mL | 1.5885 mL | 3.1769 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution 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 stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Identification and characterization of a potent and selective KDM5 inhibitor with reversible activity in cells.Nat Chem Biol.2016 Jul;12(7):531-8. th> |
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CPI-455 selectively affects H3K4 methylation in several cell models.Nat Chem Biol.2016 Jul;12(7):531-8. td> |
Crystal structure of KDM5A.Nat Chem Biol.2016 Jul;12(7):531-8. td> |
Inhibitor binding at the KDM5A active site. th> |
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KDM5 activity is increased in DTP modelsin vitroandin vivo.Nat Chem Biol.2016 Jul;12(7):531-8. td> |
KDM5 inhibition suppresses the emergence of drug-tolerant cells.Nat Chem Biol.2016 Jul;12(7):531-8. td> |