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| Targets |
KH-4-43 targets E3 CRL4 (Cullin-RING E3 ubiquitin ligase 4), a multi-subunit complex that plays a critical role in protein ubiquitination and degradation. CRL4 regulates the degradation of various substrates involved in cell cycle control, DNA repair, and tumor suppression. By inhibiting the core ligase complex, KH-4-43 disrupts CRL4-mediated ubiquitination and substrate degradation, leading to anticancer activity.
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| ln Vitro |
KH-4-43 shows potent in vitro activity against E3 CRL4 with a binding affinity (Kd) of 83 nM for ROC1-CUL4A CTD. The compound exhibits high selectivity for CRL4 over the closely related CRL1 complex (Kd = 9.4 μM for ROC1-CUL1 CTD), representing approximately 100-fold selectivity. This selectivity is important for reducing off-target effects. The compound demonstrates anticancer activity in preclinical studies.
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| ln Vivo |
KH-4-43 has shown potential in preclinical studies as an anticancer agent, particularly for tumors that exhibit dysregulated cell growth and resistance to standard therapies. By inhibiting CRL4-mediated ubiquitination, the compound may induce cell cycle arrest or apoptosis in cancer cells. However, detailed in vivo efficacy data have not been extensively reported in the available literature.
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| Enzyme Assay |
Non-cell-based binding assays for KH-4-43 typically involve surface plasmon resonance (SPR) or fluorescence polarization to measure binding affinity to CRL4 complex components. A typical protocol includes: immobilizing ROC1-CUL4A CTD protein on a sensor chip, flowing KH-4-43 at various concentrations, and calculating Kd from the response data. Selectivity is assessed by similar binding studies with ROC1-CUL1 CTD or other E3 ligase complexes.
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| Cell Assay |
Cellular assays with KH-4-43 typically involve cancer cell lines with dysregulated CRL4 activity. A representative protocol includes: culturing cancer cells, treating with KH-4-43 at various concentrations (0.1–50 μM) for 24–72 hours, assessing cell viability using MTT or CellTiter-Glo assays, evaluating CRL4 substrate accumulation by Western blot, and measuring cell cycle distribution and apoptosis by flow cytometry.
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| Animal Protocol |
In vivo animal studies with KH-4-43 typically involve xenograft mouse models of cancer. A representative protocol includes: subcutaneous implantation of cancer cells in immunodeficient mice, allowing tumors to reach a certain size, administering KH-4-43 via intraperitoneal or oral route at doses determined from pharmacokinetic studies, monitoring tumor growth and body weight, and harvesting tumors for histopathological and molecular analysis.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of KH-4-43 have not been extensively reported in the available literature. As a small molecule with a molecular weight of 422.74 g/mol, it is expected to have moderate oral bioavailability and tissue distribution. Further PK studies are needed to characterize its absorption, distribution, metabolism, and excretion profile.
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| Toxicity/Toxicokinetics |
Toxicological data for KH-4-43 are limited as the compound is in preclinical research stages. Standard safety assessments would include cytotoxicity screening, hERG channel inhibition testing, and preliminary toxicology studies in animal models. As a research compound, it is not intended for human therapeutic use.
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| References | |
| Additional Infomation |
KH-4-43 (CAS 2813310-07-3) is a valuable tool for studying the role of E3 CRL4 ubiquitin ligase in cancer biology. The high selectivity for CRL4 over CRL1 (approximately 100-fold) makes it a useful probe for dissecting CRL4-specific functions. This compound represents a potential strategy for targeting the ubiquitin-proteasome system for cancer therapy. It is also referred to as a CRL4 E3 ligase inhibitor.
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| Molecular Formula |
C19H10CLF3N2O4
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|---|---|
| Molecular Weight |
422.74
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| CAS # |
2813310-07-3
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| Appearance |
Off-white to yellow solid powder
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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 |
| 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 (~236.55 mM; with sonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.91 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 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 and add it to 400 μL PEG300 and mix well. Then add 50 μL Tween-80 to the above system and mix well. Then continue to add 450 μL of physiological saline to make up to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3655 mL | 11.8276 mL | 23.6552 mL | |
| 5 mM | 0.4731 mL | 2.3655 mL | 4.7310 mL | |
| 10 mM | 0.2366 mL | 1.1828 mL | 2.3655 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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