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Tanzisertib (formerly known as CC-930, JNK-930, JNKI-1, CC 930) is a potent, specific and and orally bioavailable JNK1/JNK2/JNK3 inhibitor that has the potential to be used for the treatment of fibrotic and infammatory indications. Tanzisertib is undergoing a Phase 1 clinical trial and may one day be used to prevent and treat dermal fibrosis. CC-930 is potent against all isoforms of JNK [Ki(JNK1) = 44 ± 3 nM, IC50(JNK1) = 61 nM, Ki(JNK2) = 6.2 ± 0.6 nM, IC50(JNK2) = 5 nM, IC50(JNK3) = 5 nM] and selective against MAP kinases ERK1 and p38a with IC50 values of 0.48 and 3.4 μM.
| Targets |
JNK3 (IC50 = 6 nM); JNK2 (IC50 = 7 nM); JNK1 (IC50 = 61 nM)
The target of Tanzisertib (CC-930) is JNK (including JNK1, JNK2, JNK3) with IC50 values of 0.15 μM, 0.18 μM, and 0.22 μM, respectively [2] |
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| ln Vitro |
Tanzisertib (CC-930) inhibits the synthesis of phospho-cJun in human PBMC stimulated by phorbol-12-myristate-13-acetate and phytohemeagglutinin (IC50=1 μM)[1]. In FC-loaded WT hepatocytes, tanzisertib (CC-930) (1-2 μM) completely abolishes apoptosis and necrosis[2]. In systemic sclerosis, tanzisertib (CC-930) inhibits the JNK pathway that is triggered by pro-fibrotic cytokines[3].
Treatment of human skin fibroblasts (HSFs) with Tanzisertib (CC-930) dose-dependently reduced the mRNA and protein expression levels of collagenⅠα1, with a 60% reduction in collagenⅠα1 protein expression at 1 μM treatment [2] - In mouse embryonic fibroblasts (MEFs), Tanzisertib (CC-930) inhibited bleomycin-induced α-smooth muscle actin (α-SMA) expression, and reduced cell proliferation (BrdU incorporation assay showed a 45% decrease in proliferation rate in the 1 μM treatment group) and migration ability (Transwell assay showed a 50% decrease in the number of migrated cells in the 1 μM treatment group) [2] - Western blot analysis indicated that Tanzisertib (CC-930) dose-dependently inhibited the phosphorylation of c-Jun (p-c-Jun), a downstream substrate of JNK, with a 70% reduction in p-c-Jun levels at 1 μM treatment, without affecting the protein levels of total JNK and total c-Jun [2] |
| ln Vivo |
Tanzisertib (CC-930) (10 and 30 mg/kg, p.o.) inhibits the production of TNFa by 23% and 77% in the acute rat LPS-induced TNFa production PK-PD model[1]. Tanzisertib (CC-930) (150 mg/kg) can cause the regression of pre-existing fibrosis while also preventing the development of fibrosis in various models[3].
In the bleomycin-induced mouse skin fibrosis model, oral administration of Tanzisertib (CC-930) at 30 mg/kg once daily for 21 days significantly reduced skin thickness (35% reduction compared with the model group) and decreased collagen deposition in the dermis (Sirius red staining showed a 40% reduction in collagen area fraction) [2] - In the animal model, drug treatment significantly downregulated the mRNA and protein expression levels of α-SMA, collagenⅠ, and TGF-β1 in skin tissues, and also significantly reduced the expression of pro-inflammatory factors IL-6 and TNF-α, inhibiting fibrosis-related signaling pathways [2] |
| Enzyme Assay |
CC-930 is kinetically competitive with ATP in the JNK-dependent phosphorylation of the protein substrate c-Jun and potent against all isoforms of JNK [Ki(JNK1) = 44 ± 3 nM, IC50(JNK1) = 61 nM, Ki(JNK2) = 6.2 ± 0.6 nM, IC50(JNK2) = 5 nM, IC50(JNK3) = 5 nM] and selective against MAP kinases ERK1 and p38a with IC50 of 0.48 and 3.4 μM respectively.
A radioactive kinase assay was used to detect the inhibitory effect of Tanzisertib (CC-930) on the activity of recombinant JNK isoforms (JNK1, JNK2, JNK3). Recombinant JNK protein was co-incubated with substrate (GST-c-Jun), ATP, and different concentrations of the drug. After incubation, phosphorylated substrate was separated, and the kinase activity inhibition rate was calculated by detecting radioactivity intensity to determine the IC50 value of each isoform [2] |
| Cell Assay |
In 96-well plates with 1 µM Tanzisertib (CC-930), fibroblasts from patients with systemic sclerosis (SSc) are incubated for 20 hours. The cells are then given an additional 4 hours of incubation at 37°C before receiving MTT at a final concentration of 1 mg/mL. All other results are normalized to untreated cells while mock-treated fibroblasts serve as the standard.
Cell culture: HSFs and MEFs were cultured in DMEM medium containing 10% fetal bovine serum at 37℃ with 5% CO₂, and seeded in 6-well plates or 96-well plates 24 hours before the experiment. Treatments were performed when the cell confluency reached 70%-80% [2] - Collagen synthesis detection: After cells were induced with bleomycin (10 ng/mL) for 24 hours, different concentrations (0.1 μM, 0.5 μM, 1 μM) of Tanzisertib (CC-930) were added and cultured for another 48 hours. CollagenⅠα1 mRNA expression was detected by quantitative real-time PCR, collagenⅠα1 protein level was detected by Western blot, or collagen deposition was observed by Sirius red staining [2] - Cell proliferation assay: Cells were seeded in 96-well plates, treated with drugs for 48 hours, added with BrdU reagent and incubated for 4 hours. The amount of BrdU incorporation was detected by enzyme-linked immunosorbent assay to calculate the cell proliferation rate [2] - Cell migration assay: Cells were seeded in the upper chamber of Transwell inserts, the lower chamber was filled with medium containing 10% fetal bovine serum, and the upper chamber was added with serum-free medium containing different concentrations of drugs. After 24 hours of culture, cells were fixed, stained, and the number of cells that migrated through the membrane was counted [2] - Protein expression detection: After cells were treated with drugs, total protein was extracted by lysis, followed by SDS-PAGE electrophoresis, membrane transfer, blocking, incubation with primary antibodies against p-JNK, JNK, p-c-Jun, c-Jun, α-SMA, etc., then incubation with secondary antibodies, and finally protein bands were detected by chemiluminescence [2] |
| Animal Protocol |
A modified version of the bleomycin-induced dermal fibrosis model is used to assess the regression of fibrosis on inhibition of JNK. In this model, significant dermal fibrosis is already present three weeks after the start of the challenge and is treated with bleomycin. The results of six different groups, comprising a total of 40 mice, are analyzed. NaCl is subcutaneously injected into the first group of mice for a total of six weeks. In order to assess the level of fibrosis prior to treatment and to prevent spontaneous fibrosis regression, the second group receives injections of bleomycin for 3 weeks, followed by injections of NaCl for an additional 3 weeks. After six weeks of bleomycin injections, the third group of mice is euthanized. The final three weeks of a continuous six-week challenge with bleomycin are spent administering Tanzisertib (CC-930) to the fourth and fifth groups at doses of 50 mg/kg and 150 mg/kg, respectively. The sixth group is a positive control group made up of mice that were given bleomycin for six weeks before being given imatinib at a dose of 50 mg/kg for the final three weeks.
Animal model establishment: C57BL/6 mice were subcutaneously injected with bleomycin (100 μg/100 μL) on the back three times a week for 4 weeks to induce skin fibrosis model; the control group was injected with the same volume of normal saline [2] - Drug administration: From the first day of bleomycin injection, Tanzisertib (CC-930) was dissolved in normal saline containing 0.5% carboxymethylcellulose sodium, and administered orally to model group mice at a dose of 30 mg/kg once daily for 21 days; the control group and model group were given the same volume of vehicle [2] - Sample collection: After the administration, mice were sacrificed, back skin tissues were collected, part of which was fixed in 4% paraformaldehyde for pathological sections, and part was stored at -80℃ for RNA and protein extraction [2] |
| References |
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| Additional Infomation |
Tanzisertib has been used in studies to treat diseases such as fibrosis, discoid lupus erythematosus, pulmonary fibrosis, interstitial lung disease, and interstitial lung disease. Tanzisertib (CC-930) is a selective JNK kinase inhibitor that specifically blocks the activation of the JNK signaling pathway [2]. Abnormal activation of the JNK pathway is closely related to the occurrence and development of fibrotic diseases. It can promote the expression of pro-fibrotic factors (such as TGF-β1 and collagen) and pro-inflammatory factors by regulating the activity of downstream transcription factors (such as c-Jun) [2]. In reference [2], Tanzisertib (CC-930) was used in studies on the treatment of skin fibrosis, providing an experimental basis for the development of drugs for fibrosis-related diseases [2].
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| Molecular Formula |
C21H23F3N6O2
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| Molecular Weight |
448.44
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| Exact Mass |
448.183
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| Elemental Analysis |
C, 56.24; H, 5.17; F, 12.71; N, 18.74; O, 7.14
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| CAS # |
899805-25-5
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| Related CAS # |
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| PubChem CID |
11597537
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| Appearance |
White to off-white solid powder
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| Density |
1.6±0.1 g/cm3
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| Boiling Point |
626.4±65.0 °C at 760 mmHg
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| Flash Point |
332.6±34.3 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.713
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| LogP |
2.08
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
32
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| Complexity |
618
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| Defined Atom Stereocenter Count |
1
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| SMILES |
N(C1C(F)=CC(F)=CC=1F)C1=NC2C=NC(=NC=2N1[C@@H]1COCC1)N[C@@H]1CC[C@@H](O)CC1
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| InChi Key |
IBGLGMOPHJQDJB-MOKVOYLWSA-N
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| InChi Code |
InChI=1S/C21H23F3N6O2/c22-11-7-15(23)18(16(24)8-11)28-21-27-17-9-25-20(26-12-1-3-14(31)4-2-12)29-19(17)30(21)13-5-6-32-10-13/h7-9,12-14,31H,1-6,10H2,(H,27,28)(H,25,26,29)/t12?,13-,14?/m0/s1
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| Chemical Name |
4-[[9-[(3S)-oxolan-3-yl]-8-(2,4,6-trifluoroanilino)purin-2-yl]amino]cyclohexan-1-ol
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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) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.57 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 (5.57 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 (5.57 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 | 2.2300 mL | 11.1498 mL | 22.2995 mL | |
| 5 mM | 0.4460 mL | 2.2300 mL | 4.4599 mL | |
| 10 mM | 0.2230 mL | 1.1150 mL | 2.2300 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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