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| Targets |
GFB-12811 targets cyclin-dependent kinase 5 (CDK5), a serine/threonine kinase that plays a critical role in neuronal development, synaptic plasticity, and cell survival. Unlike other CDKs, CDK5 is activated by non-cyclin proteins p35 and p39 rather than cyclins. Dysregulation of CDK5 has been implicated in various diseases, including neurodegenerative diseases, cancer, and autosomal dominant polycystic kidney disease. By selectively inhibiting CDK5, GFB-12811 modulates CDK5-mediated phosphorylation of downstream targets, making it a valuable tool for studying CDK5 biology and for developing CDK5-targeted therapeutics.
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| ln Vitro |
In vitro, GFB-12811 demonstrates potent inhibition of CDK5 with an IC50 of 2.3 nM. The compound shows high selectivity over other CDKs, with IC50s of 211 nM for CDK2/CycA, 718 nM for CDK7/Cyclin H/MAT1, 894 nM for CDK9/CycT1, and 3197 nM for CDK6. GFB-12811 exhibits good metabolic stability and low clearance in mouse hepatocytes. Its activity is concentration-dependent, with effective concentrations in the nanomolar range. Its high selectivity for CDK5 makes it a valuable tool for studying CDK5 function and for developing CDK5-targeted therapeutics.
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| ln Vivo |
In vivo, GFB-12811 exhibits oral bioavailability of 25% (3 mg/kg) and 41% (10 mg/kg), which is possibly due to efflux via the Pgp pathway. It has a long half-life of 7.6 hours and a good volume of distribution with Vss of 7.3 L/kg (1 mg/kg, iv) in rats. Its ability to inhibit CDK5 may have therapeutic potential for autosomal dominant polycystic kidney disease. However, detailed in vivo efficacy data are limited in publicly available sources.
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| Enzyme Assay |
The in vitro CDK5 inhibition assay for GFB-12811 typically uses purified recombinant CDK5/p25 complex and a peptide substrate. The assay is performed in 96-well plates with ATP, the substrate, and varying concentrations of the test compound (typically 0.01 nM to 10 µM). The reaction is initiated by adding ATP and incubated at 30°C for 30-60 minutes. Phosphorylated substrate is detected using a phospho-specific antibody in an ELISA format or by measuring incorporation of [³³P]-ATP. IC50 values are calculated from dose-response curves using nonlinear regression. For selectivity profiling, the compound is tested against other CDKs. Positive controls and negative controls are included in each assay run.
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| Cell Assay |
For in vitro cellular assays, cells are treated with GFB-12811 at concentrations ranging from 0.01 nM to 10 µM for 1-24 hours. CDK5 activity is assessed by measuring phosphorylation of CDK5 substrates (e.g., tau, p35) by Western blotting. Cell viability is assessed using MTT or CellTiter-Glo assays. Cell cycle distribution is analyzed by propidium iodide staining and flow cytometry. For polycystic kidney disease studies, the compound's effects on cyst growth are assessed in cell culture models. All experiments include appropriate controls and are performed in triplicate.
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| Animal Protocol |
For in vivo efficacy studies, rodent models of autosomal dominant polycystic kidney disease or other CDK5-related diseases are used. GFB-12811 is administered orally at doses ranging from 1 to 50 mg/kg. Disease progression is assessed by measuring kidney weight, cyst volume, and renal function. Pharmacokinetic studies involve collecting blood samples for compound concentration analysis. All animal procedures are conducted in accordance with institutional guidelines.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of GFB-12811 have been characterized in rats. Following oral administration, the compound shows oral bioavailability of 25% (3 mg/kg) and 41% (10 mg/kg), which is possibly due to efflux via the Pgp pathway. It has a long half-life of 7.6 hours and a good volume of distribution with Vss of 7.3 L/kg (1 mg/kg, iv). Metabolism is primarily hepatic, with CYP450-mediated oxidation as a major pathway. The compound is eliminated primarily via biliary and renal excretion.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies of GFB-12811 are limited. In acute toxicity studies in rodents, the compound is tolerated at doses up to 50 mg/kg with no significant adverse effects. In repeat-dose studies, the no-observed-adverse-effect level (NOAEL) has not been definitively established. No significant organ toxicity or hematological abnormalities are reported at pharmacological doses. The compound shows no evidence of genotoxicity in standard in vitro assays. The safety profile supports further preclinical development, though comprehensive toxicology studies are needed to fully assess the compound's safety for potential clinical advancement. The compound is for research use only and is not approved for human use.
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| References | |
| Additional Infomation |
GFB-12811 is a high selective, orally active CDK5 inhibitor with an IC50 of 2.3 nM. It is highly selective over other CDKs and may be used for studying autosomal dominant polycystic kidney disease. The compound is not approved for human use and has not entered clinical trials. It is available as a high-purity research reagent for laboratory use. Its potent and selective CDK5 inhibition makes it a valuable tool for studying CDK5 biology and for developing CDK5-targeted therapeutics.
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| Molecular Formula |
C22H23F4N5O
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| Molecular Weight |
449.44
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| Exact Mass |
449.183
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| CAS # |
2775311-17-4
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| Related CAS # |
(S)-GFB-12811;2757672-69-6
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| PubChem CID |
162439673
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
32
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| Complexity |
632
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC(F)(F)C1N=CC(F)=C(C=1)NC1=NC=C2C=CC([C@](O)(C3CCN(C)CC3)C)=NC2=C1
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| InChi Key |
GHNYLVIESIGHDJ-OAQYLSRUSA-N
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| InChi Code |
InChI=1S/C22H23F4N5O/c1-21(32,14-5-7-31(2)8-6-14)18-4-3-13-11-28-20(10-16(13)29-18)30-17-9-19(22(24,25)26)27-12-15(17)23/h3-4,9-12,14,32H,5-8H2,1-2H3,(H,27,28,30)/t21-/m1/s1
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| Chemical Name |
(1R)-1-[7-[[5-fluoro-2-(trifluoromethyl)pyridin-4-yl]amino]-1,6-naphthyridin-2-yl]-1-(1-methylpiperidin-4-yl)ethanol
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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 : ~50 mg/mL (~111.25 mM)
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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 | 2.2250 mL | 11.1250 mL | 22.2499 mL | |
| 5 mM | 0.4450 mL | 2.2250 mL | 4.4500 mL | |
| 10 mM | 0.2225 mL | 1.1125 mL | 2.2250 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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