| Size | Price | Stock | Qty |
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| 25mg |
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| Targets |
KDM5 histone demethylase
The primary target of KDM5-C70 is the KDM5 family of histone demethylases (also known as JARID1), which play crucial roles in regulating gene expression through the demethylation of lysine residues on histone proteins. KDM5 enzymes (KDM5A, KDM5B, KDM5C, KDM5D) are Jumonji C (JmjC) domain-containing demethylases that specifically remove methyl groups from histone H3 lysine 4 (H3K4), a mark associated with active transcription. KDM5-C70 is a pan-KDM5 inhibitor with IC₅₀ values of 0.3, 0.3, and 0.58 μM for KDM5A, KDM5B, and KDM5C, respectively. Overexpression of KDM5 is implicated in tumor progression, drug resistance, and stem cell maintenance. |
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| ln Vitro |
After 7 days of treatment at increasing concentrations, KDM5-C70 (10-9-10-5 M; 7 days; MM.1S myeloma cells) therapy demonstrated antiproliferative effects (expectedly, KDM5-C70 lowered viability/proliferation at ~20 50%) micron)[1]. Treatment with KDM5-C70 (50 μM; 7 days; MM.1S myeloma cells) reduced retinoblastoma protein (Rb) phosphorylation levels, but did not affect overall levels of phosphorylated Rb (pRb), suggesting poor cell cycle progress [1]. At a 50 μM inhibitor dose, chromatin immunoprecipitation and next-generation sequencing revealed an increase in H3K4me3 levels surrounding the KDM5-C70 transcription start site, although GSK467A did not alter appreciably [1].
In vitro, KDM5-C70 increases H3K4me3 levels in myeloma cells. Treatment of MCF7 and MDA-MB-231 breast cancer cells with KDM5-C70 significantly increased global levels of H3K4me3 while having little impact on H3K4me2/me1 or modifications regulated by other histone lysine demethylases. The compound has an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. As a prodrug, KDM5-C70 has enhanced cellular permeability compared to KDM5-C49. |
| ln Vivo |
In vivo, KDM5-C70 is used to study the role of KDM5 enzymes in cancer, as KDM5 overexpression is implicated in tumor progression, drug resistance, and stem cell maintenance. By targeting KDM5 enzymes, this compound modulates histone methylation levels, making it a valuable tool for studying gene expression and chromatin dynamics. However, specific in vivo efficacy data from animal models is not detailed in the provided sources.
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| Enzyme Assay |
Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe(2+)-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families. Whereas GSK-J1, a previously identified KDM6 inhibitor, showed about sevenfold less inhibitory activity toward KDM5B than toward KDM6 proteins, KDM5-C49 displayed 25-100-fold selectivity between KDM5B and KDM6B. The cell-permeable derivative KDM5-C70 had an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. The selective inhibitor GSK467 exploited unique binding modes, but it lacked cellular potency in the myeloma system. Taken together, these structural leads deliver multiple starting points for further rational and selective inhibitor design[1].
For KDM5 demethylase inhibitors, standard cell-free assays involve measuring the demethylase activity of recombinant KDM5 enzymes using biotinylated histone H3 peptides (H3K4me3) as substrates. The compound is incubated with the enzyme and substrate, and the demethylation reaction is detected by AlphaScreen, ELISA, or mass spectrometry to determine IC₅₀ values. |
| Cell Assay |
Cell Viability Assay[1]
Cell Types: MM.1S Myeloma Cells Tested Concentrations: 10-9-10-5 M Incubation Duration: 7 days Experimental Results: Antiproliferative effect was shown after 7 days of treatment at increasing concentrations. Western Blot Analysis[1] Cell Types: MM.1S Myeloma Cells Tested Concentrations: 50 μM Incubation Duration: 7 days Experimental Results: diminished phosphorylation levels of retinoblastoma protein (Rb). For KDM5 inhibitors, standard cellular assays involve treatment of cancer cell lines with the test compound for 7 days at increasing concentrations (10⁻⁹ to 10⁻⁵ M). H3K4me3 levels are measured by western blot or immunofluorescence. Cell viability (MTT or CellTiter-Glo) and proliferation are assessed to determine antiproliferative effects. Selectivity for H3K4me3 over other histone marks is assessed by measuring H3K4me2/me1 and other modifications. |
| Animal Protocol |
For in vivo evaluation of KDM5 inhibitors, standard animal models include tumor xenograft models using cancer cell lines sensitive to KDM5 inhibition (e.g., myeloma, breast cancer). The compound is typically administered orally or intraperitoneally for 2-4 weeks. Tumor growth, H3K4me3 levels, apoptosis markers, and survival are assessed.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic data for KDM5-C70 is not extensively provided in the available sources. The compound has a molecular weight of 336.43 and formula C₁₇H₂₈N₄O₃. As a prodrug of KDM5-C49, it has enhanced cellular permeability. The compound has a purity of 98.82%. Comprehensive PK studies would be required for therapeutic development.
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| Toxicity/Toxicokinetics |
Detailed toxicology data for KDM5-C70 is not provided in the available sources. As a research compound targeting epigenetic regulators, standard preclinical toxicology would be required for therapeutic development. The compound's effects on histone methylation in normal cells would need to be evaluated. The compound is for research use only and not for therapeutic applications.
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| References | |
| Additional Infomation |
The mechanisms by which cells regulate gene and protein expression are complex and diverse. The regulation of mRNA 3' untranslated region (UTR) processing has been shown to play a crucial role in development and disease. However, how cells select different mRNA forms remains unclear. We found that the Saccharomyces cerevisiae lysine demethylase Jhd2 (also known as KDM5) can recruit 3'UTR processing mechanisms and promote alterations in the 3'UTR length of certain genes in a demethylase-dependent manner. Jhd2 interactions with chromatin and RNA suggest that Jhd2 influences the selection of polyadenylation sites through transcriptional coupling mechanisms. Furthermore, its mammalian homolog, KDM5B (also known as JARID1B or PLU1), rather than KDM5A (also known as JARID1A or RBP2), promotes the shortening of the CCND1 transcript in breast cancer cells. Consistent with these results, KDM5B expression is associated with CCND1 shortening in human breast tumor tissues. Conversely, both KDM5A and KDM5B are involved in DICER1 elongation. Our findings suggest a new function for this family of demethylases and a novel targetable mechanism for 3'UTR processing. [2]
KDM5-C70 is a cell-permeable derivative and ethyl ester prodrug of KDM5-C49 (GS-080), a potent, selective, and cell-permeable pan-KDM5 histone demethylase inhibitor. It has IC₅₀ values of 0.3, 0.3, and 0.58 μM for KDM5A, KDM5B, and KDM5C, respectively. The compound increases H3K4me3 levels in myeloma cells and has an antiproliferative effect. No regulatory approval has been identified. |
| Molecular Formula |
C17H28N4O3
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|---|---|
| Molecular Weight |
336.436
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| Exact Mass |
336.216
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| Elemental Analysis |
C, 60.69; H, 8.39; N, 16.65; O, 14.27
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| CAS # |
1596348-32-1
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| PubChem CID |
90094283
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| Appearance |
Light yellow to yellow liquids
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
466.6±45.0 °C at 760 mmHg
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| Flash Point |
236.0±28.7 °C
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| Vapour Pressure |
0.0±1.2 mmHg at 25°C
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| Index of Refraction |
1.525
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| LogP |
0.75
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
24
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| Complexity |
390
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C([H])([H])N([H])C([H])([H])C1C([H])=C(C(=O)OC([H])([H])C([H])([H])[H])C([H])=C([H])N=1)N(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])[H]
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| InChi Key |
WCILOMUUNVPIKQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H28N4O3/c1-5-21(10-9-20(3)4)16(22)13-18-12-15-11-14(7-8-19-15)17(23)24-6-2/h7-8,11,18H,5-6,9-10,12-13H2,1-4H3
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| Chemical Name |
ethyl 2-(((2-((2-(dimethylamino)ethyl)(ethyl)amino)-2-oxoethyl)amino)methyl)isonicotinate
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| Synonyms |
KDM5 C70 KDM5C70 KDM5-C70
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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) |
DMSO : ~100 mg/mL (~297.24 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.43 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.43 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (7.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9723 mL | 14.8615 mL | 29.7230 mL | |
| 5 mM | 0.5945 mL | 2.9723 mL | 5.9446 mL | |
| 10 mM | 0.2972 mL | 1.4861 mL | 2.9723 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.
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