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| Targets |
Senexin C targets cyclin-dependent kinase 8 (CDK8) and cyclin-dependent kinase 19 (CDK19), which are members of the mediator complex that regulate transcription. CDK8/19 are involved in the regulation of gene expression, including genes important for cancer cell growth and survival. By inhibiting CDK8/19, Senexin C modulates transcriptional programs and exhibits anticancer activity.
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| ln Vitro |
Senexin C (compound 20a) has strong and highly specific CDK8/19 inhibitory action (IC50 of 108 nM for MV4-11-Luc cells and 56 nM for 293-NFκB-Luc cells, respectively) [1]. In various kinase tests, sensexin C (2 µM) demonstrates potency (IC50 = 3.6 nM for CD8/CycC, Kd = 1.4 nM for CD8/CycC, Kd = 2.9 nM for CDK19/CycC) [1]. Senexin C (1 µM, 3 hours) inhibits the expression of cellular genes that are dependent on CDK8/19 [1].
In vitro, Senexin C inhibits the growth of MV4-11 leukemia cells with good tolerability. It shows activity in 293-NFκB-Luc cells with IC50 = 56 nM. It is more metabolically stable and potent than Senexin B. These in vitro activities demonstrate its potential as an anticancer agent. |
| ln Vivo |
Senexin C exhibits good oral bioavailability at doses of 100 mg/kg orally and 2.5 mg/kg intravenously [1]. Senexin C (40 mg/kg; oral; twice daily for 4 weeks) is well-tolerated and inhibits the growth of MV4-11 AML in the systemic form [1]. Senexin C pharmacokinetic parameters in female Balb/c mice aged eight weeks [1]. Parameter IV (2.5 mg/kg) po (100 mg/kg) Plasma Tumor Plasma Tumor C0 (μg/mL) 503 Kel (h-1) 0.93 0.06 0.2 0.1 T1/2 (h) 0.75 12.1 3.53 7.27 Tmax (h) 0.58 12 12 Cmax (ng/mL or ng/g) 488 144 5728 AUC0-24 h (ng xh/ml or ng xh/g) 331 6408 2182 88,600 F% 16.5% 34.6% Eight-week-old female Balb/c mice (CT26 tumor model); 2.5 mg/kg intravenously (10 mg/mL Senexin C solution in 5% glucose); 100 mg/kg orally (10 mg/mL Senexin C solution in 30% propylene glycol/ 70% PEG-400 carrier) [1].
In vivo, Senexin C is orally active and shows a strong tumor-enrichment pharmacokinetic (PK) profile and tumor-pharmacodynamic (PD) marker responses. It inhibits the growth of MV4-11 leukemia cells with good tolerability. Specific in vivo efficacy data are limited in publicly available sources. The compound is being studied for cancer research applications. |
| Enzyme Assay |
In vitro kinase assays are used to characterize Senexin C's inhibition of CDK8 and CDK19. The kinases are incubated with the compound and ATP substrate, and kinase activity is measured. IC50 values are determined from dose-response curves. Selectivity for CDK8/19 over other kinases is assessed.
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| Cell Assay |
RT-PCR[1]
Cell Types: 293 cells Tested Concentrations: 1 µM Incubation Duration: 3 hrs (hours) Experimental Results: Shows inhibition of CDK8/19-dependent cellular gene expression. Cell-based assays for Senexin C are conducted in cancer cell lines including MV4-11 leukemia cells. Cells are treated with the compound at various concentrations, and cell viability, proliferation, and apoptosis are assessed. NFκB-Luc reporter assays are used to measure transcriptional activity (IC50 = 56 nM). |
| Animal Protocol |
Animal/Disease Models: Eightweeks old female balb/c (Bagg ALBino) mouse (CT26 tumor model) [1]
Doses: 2.5 mg/kg (10 mL/kg 2.5 mg/mL Senexin C solution in 5% glucose), 100 mg/kg ( 10 mL/kg 10 mg/mL Senexin C solution in 30% propylene glycol/70% PEG-400 vehicle) Dosing: 2.5 mg/kg IV; 100 mg/kg PO Experimental Results: Demonstrated good oral biologic Utilization. Animal/Disease Models: 8weeks old female NSG mice (AML model) [1] Doses: 40 mg/kg Route of Administration: po; twice a day for 4 weeks Experimental Results: Inhibited the systemic growth of MV4-11 AML, with good tolerance. In vivo animal experiments with Senexin C are conducted in xenograft models. The compound is administered orally, and tumor growth inhibition is assessed. Pharmacokinetic and pharmacodynamic analyses are performed to evaluate tumor enrichment and target engagement. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of Senexin C include oral activity and a strong tumor-enrichment PK profile. The compound has molecular weight 449.5 and molecular formula C28H27N5O. Storage: cool, dry place. Specific PK parameters have not been extensively reported.
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| Toxicity/Toxicokinetics |
Safety and toxicology data for Senexin C indicate good tolerability in preclinical studies. The compound is for research use only and is not approved for human therapeutic use. Standard laboratory safety precautions should be followed when handling the compound.
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| References | |
| Additional Infomation |
Senexin C has CAS number 2375554-02-0, molecular formula C28H27N5O, and molecular weight 449.5. It is a novel, orally active, and specific CDK8/19 inhibitor with potential anticancer activity. It is more metabolically stable and potent than Senexin B. Purity: ≥98%. Not for human use; for research purposes only.
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| Molecular Formula |
C28H27N5O
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| Molecular Weight |
449.546885728836
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| Exact Mass |
449.221
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| CAS # |
2375554-02-0
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| PubChem CID |
146403432
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
34
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| Complexity |
740
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N(C1=CC=NC2C=CC(C#N)=CC1=2)CCC1C=CC2C=C(C(N3CCN(C)CC3)=O)C=CC=2C=1
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| InChi Key |
AFUHWZUYZJGVKM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H27N5O/c1-32-12-14-33(15-13-32)28(34)24-6-5-22-16-20(2-4-23(22)18-24)8-10-30-27-9-11-31-26-7-3-21(19-29)17-25(26)27/h2-7,9,11,16-18H,8,10,12-15H2,1H3,(H,30,31)
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| Chemical Name |
4-[2-[6-(4-methylpiperazine-1-carbonyl)naphthalen-2-yl]ethylamino]quinoline-6-carbonitrile
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 2.2244 mL | 11.1222 mL | 22.2445 mL | |
| 5 mM | 0.4449 mL | 2.2244 mL | 4.4489 mL | |
| 10 mM | 0.2224 mL | 1.1122 mL | 2.2244 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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