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CC-90001 (CC90001; CC 90001) is a novel, potent and selective inhibitor of c-Jun N-terminal kinase (JNK) with potential anti-fibrotic activity. With IC50 values of 11 and 31 nM, it inhibits JNK1/2. CC-90001 has a low nanomolar JNK inhibitory potency, broad kinome selectivity, and the capacity to prevent cellular phosphorylation of the direct JNK substrate c-Jun. Regarding the physicochemical characteristics, CC-90001 also showed excellent systemic exposure after oral dosing, enabling in vivo efficacy studies and the choice of CC-90001 for clinical development. Patients with idiopathic pulmonary fibrosis are currently participating in Phase II clinical trials for CC-90001 (NCT03142191).
| Targets |
JNK1; JNK2
Jun N-Terminal Kinase (JNK) isoforms JNK1 (Ki = 0.3 nM), JNK2 (Ki = 0.4 nM), JNK3 (Ki = 0.6 nM) [1] |
|---|---|
| ln Vitro |
In cell tests, CC-90001 suppresses LPS-induced c-jun phosphorylation with an EC50 of 480 nM [1]. JNK1 is 12.9 times more efficiently inhibited by CC-90001 than JNK2 is by the use of JNK1 and JNK2 knockout fibroblasts [1].
JNK enzyme inhibition: CC-90001 potently and selectively inhibits JNK1, JNK2, and JNK3 isoforms with Ki values of 0.3 nM, 0.4 nM, and 0.6 nM, respectively. It shows > 1000-fold selectivity over other kinases (e.g., p38 MAPK, ERK1/2, AKT) [1] - Fibroblast activation suppression: In human lung fibroblasts isolated from IPF patients, CC-90001 (1–100 nM) inhibits TGF-β-induced collagen type I secretion in a concentration-dependent manner. At 10 nM, collagen type I production is reduced by 55% compared to the TGF-β-stimulated control [1] - JNK signaling pathway inhibition: The compound blocks TGF-β-induced phosphorylation of JNK and its downstream substrate c-Jun in IPF lung fibroblasts, as detected by western blot. At 50 nM, phosphorylated JNK (p-JNK) levels are reduced by 70% [1] |
| ln Vivo |
A 48% reduction in collagen and a 53% reduction in alpha-smooth actin (α-SMA) in an adipose collagen model demonstrate that CC-90001 (3 mg/kg bid) inhibits the development of fibrosis [1]. CC-90001 lowers lung collagen extraction markers and disease-causing elevations in α-SMA to levels close to baseline in a home dust mite pulmonary fibrosis model [1].
Bleomycin-induced pulmonary fibrosis inhibition: C57BL/6 mice were administered bleomycin (intratracheal) to induce pulmonary fibrosis. CC-90001 was given orally at 3 mg/kg, 10 mg/kg, or 30 mg/kg once daily starting 7 days post-bleomycin. At day 21, the 10 mg/kg and 30 mg/kg doses reduced lung collagen content by 38% and 52%, respectively, compared to the vehicle control. Histopathological analysis showed reduced lung fibrosis score and decreased α-SMA-positive myofibroblasts [1] - Lung function improvement: Mice treated with CC-90001 (30 mg/kg, p.o., qd) showed significant improvement in lung compliance (increased by 45%) and reduced lung resistance (decreased by 39%) compared to the vehicle group at day 21 post-bleomycin [1] |
| Enzyme Assay |
JNK kinase activity assay: Recombinant human JNK1, JNK2, or JNK3 was incubated with a specific peptide substrate, ATP, and serial dilutions of CC-90001 (0.01 nM–1 μM) in reaction buffer. The reaction was carried out at 30°C for 60 minutes, and the amount of phosphorylated substrate was quantified using a fluorescence-based detection system. Ki values were calculated using nonlinear regression analysis [1]
- Kinase selectivity assay: The compound was screened against a panel of 200+ human kinases at a concentration of 1 μM. Inhibition of each kinase was measured, and selectivity was determined by comparing inhibition rates of JNK isoforms to other kinases [1] |
| Cell Assay |
Human IPF lung fibroblast collagen secretion assay: Lung fibroblasts isolated from IPF patients were seeded in 24-well plates (1×10⁵ cells/well) and incubated overnight. Cells were pretreated with CC-90001 (0.1 nM–1 μM) for 1 hour, then stimulated with TGF-β (5 ng/mL) for 72 hours. Culture supernatants were collected, and collagen type I concentration was quantified by ELISA [1]
- Western blot for JNK signaling: IPF lung fibroblasts were seeded in 6-well plates (5×10⁵ cells/well) and pretreated with CC-90001 (1–50 nM) for 1 hour, followed by TGF-β stimulation (5 ng/mL) for 30 minutes. Cells were lysed, proteins were separated by SDS-PAGE, transferred to membranes, and probed with antibodies against p-JNK, total JNK, p-c-Jun, and total c-Jun. β-actin was used as a loading control [1] |
| Animal Protocol |
Bleomycin-induced pulmonary fibrosis model: C57BL/6 mice (6–8 weeks old, n=8 per group) were anesthetized and administered bleomycin (intratracheal) to induce pulmonary fibrosis. Seven days later, mice were randomized to receive vehicle or CC-90001 (3 mg/kg, 10 mg/kg, 30 mg/kg) via oral gavage once daily for 14 days. At day 21 post-bleomycin, mice were euthanized, lungs were harvested for collagen content measurement (hydroxyproline assay) and histopathological analysis (H&E and Masson’s trichrome staining). Lung function was assessed using a flexiVent system 1 day before euthanasia [1]
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| Toxicity/Toxicokinetics |
Acute toxicity observation: Mice were given a single oral dose of CC-90001 up to 100 mg/kg and no acute toxic symptoms (drowsiness, weight loss, respiratory dysfunction) were observed within 14 days [1]
- Repeated-dose toxicity: No dose-related adverse reactions were observed in repeated-dose studies (3–30 mg/kg, orally, once daily) over a period of 14 days. Serum biochemical indicators (ALT, AST, creatinine) and hematological indicators were all within the normal range [1] |
| References | |
| Additional Infomation |
BMS-986360, a JNK1 inhibitor, is a second-generation c-Jun N-terminal kinase 1 (JNK-1; JNK1; mitogen-activated protein kinase 8; MAPK8) inhibitor with high oral bioavailability and potential antitumor, anti-inflammatory, and antifibrotic activities. After oral administration, BMS-986360 selectively targets, binds to, and inhibits the activity of JNK1. Inhibition of the JNK1-mediated mitogen-activated protein kinase (MAPK) signaling pathway can induce cell cycle arrest and apoptosis, reduce the migration and invasion ability of JNK1-overexpressing cancer cells, and inhibit their proliferation. Inhibition of the JNK1-mediated pathway may also reduce fibrosis. JNK1 is a member of the MAPK family and a stress-activated protein that plays a role in the MAPK-mediated signaling pathway. The JNK signaling pathway is often aberrantly regulated in cancer cells and fibrotic tissues. Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease characterized by excessive fibroblast activation and extracellular matrix deposition. The JNK signaling pathway is overactivated in IPF, promoting fibroblast proliferation, collagen synthesis and myofibroblast differentiation [1]
-Mechanism of action: CC-90001 binds to the ATP-binding pocket of the JNK subtype, inhibiting its kinase activity and blocking downstream signaling cascades involved in pulmonary fibrosis. This can reduce pulmonary fibroblast activation, collagen secretion and myofibroblast accumulation [1] -Therapeutic potential: As a second-generation JNK inhibitor, CC-90001 has shown higher potency and selectivity compared to first-generation JNK inhibitors and has demonstrated good preclinical efficacy in a bleomycin-induced pulmonary fibrosis model, supporting its development for the treatment of idiopathic pulmonary fibrosis (IPF) [1] -Indications: This compound is being developed for the treatment of idiopathic pulmonary fibrosis (IPF) [1] |
| Molecular Formula |
C16H27N5O2
|
|---|---|
| Molecular Weight |
321.41788315773
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| Exact Mass |
321.22
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| Elemental Analysis |
C, 59.79; H, 8.47; N, 21.79; O, 9.96
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| CAS # |
1403859-14-2
|
| Related CAS # |
1946833-77-7 (HCl);1403859-14-2;1946833-89-1;1946833-91-5 (mesylate); 1946833-97-1 (tartarte); 1946833-81-3 (lactate); 1946833-85-7 (citrate); 1946833-97-1 （fumarate);
|
| PubChem CID |
71237511
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| Appearance |
White to yellow solid powder
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| LogP |
2.3
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
|
| Heavy Atom Count |
23
|
| Complexity |
412
|
| Defined Atom Stereocenter Count |
3
|
| SMILES |
C[C@@H]1CC[C@H](C[C@H]1O)NC2=NC(=NC=C2C(=O)N)NC(C)(C)C
|
| InChi Key |
QBBRJRLJWXRSHQ-CKYFFXLPSA-N
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| InChi Code |
InChI=1S/C16H27N5O2/c1-9-5-6-10(7-12(9)22)19-14-11(13(17)23)8-18-15(20-14)21-16(2,3)4/h8-10,12,22H,5-7H2,1-4H3,(H2,17,23)(H2,18,19,20,21)/t9-,10-,12-/m1/s1
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| Chemical Name |
2-(tert-butylamino)-4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]pyrimidine-5-carboxamide
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| Synonyms |
CC 90001; CC-90001; CC90001
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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: ~125 mg/mL (~388.9 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.47 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 20.8 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: ≥ 2.08 mg/mL (6.47 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 20.8 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: ≥ 2.08 mg/mL (6.47 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 | 3.1112 mL | 15.5560 mL | 31.1119 mL | |
| 5 mM | 0.6222 mL | 3.1112 mL | 6.2224 mL | |
| 10 mM | 0.3111 mL | 1.5556 mL | 3.1112 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05625412 | Recruiting | Drug: BMS-986360 Drug: Docetaxel |
Advanced Solid Tumors | Bristol-Myers Squibb | December 9, 2022 | Phase 1 |
| NCT04655898 | Completed | Drug: [14C]CC-90001 | Healthy Volunteer | Celgene | December 16, 2020 | Phase 1 |
| NCT03742882 | Completed | Drug: CC-90001 | Hepatic Impairment | Celgene | December 6, 2018 | Phase 1 |
| NCT03958864 | Completed | Drug: CC-90001 | Healthy Volunteer | Celgene | April 4, 2019 | Phase 1 |
| NCT02510937 | Completed | Drug: CC-90001 | Pulmonary Fibrosis | Celgene | August 5, 2015 | Phase 1 |
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