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Purity: ≥98%
CEP33779 is a novel, potent, orally bioactive, highly selective inhibitor of JAK2 (Janus kinase) with potential antitumor and anti-inflammatory activity. It inhibits JAK2 with an IC50 of 1.8 nM, and exhibits >40- and >800-fold selectivity for JAK2 over JAK1 and TYK2. CEP33779 showed high activity in mice with collagen-induced arthritis (CIA) and collagen-antibody induced arthritis (CAIA). It induced regression of established colorectal tumors, reduced angiogenesis, and reduced proliferation of tumor cells. The ability of CEP-33779 to suppress growth of colorectal tumors by inhibiting the IL-6/JAK2/STAT3 signaling suggests a potential therapeutic utility of JAK2 inhibitors in multiple tumors types, particularly those with a strong inflammatory component.
| Targets |
From [1] (JAK2-focused assays):
- CEP-33779 is a selective ATP-competitive inhibitor of Janus kinase 2 (JAK2);
- IC50 for JAK2 (recombinant human) = 1.5 nM; Ki for JAK2 = 0.8 nM;
- IC50 for JAK1 = 220 nM, IC50 for JAK3 = 280 nM, IC50 for TYK2 = 210 nM (≥147/187/140-fold selectivity for JAK2 over JAK1/JAK3/TYK2);
- No significant inhibition of non-JAK kinases (EGFR: IC50 > 1000 nM; SRC: IC50 > 800 nM) [1]
- From [3] (ABCB1-focused assays): - Inhibits ATP-binding cassette subfamily B member 1 (ABCB1, P-glycoprotein) transport function; - IC50 for ABCB1-mediated rhodamine 123 efflux inhibition = 3.2 μM (in KB-V1 cells); - No direct inhibition of ABCB1 ATPase activity (Ki > 10 μM) [3] - From [2]: No new target data; focuses on JAK2 inhibition in colorectal cancer (CRC) [2] |
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| ln Vitro |
At non-toxic concentrations, P-glycoprotein-overexpressing multidrug-resistant cells' overexpression sensitivity to CEP-33779's anti-cancer substrates is markedly increased. Through inhibition of P-glycoprotein transport function overexpression, CEP-33779 drastically lowers doxorubicin efflux and increases intracellular accumulation [3].
JAK2-positive hematological cancer activity (from [1]): In JAK2V617F-positive cells (HEL: erythroleukemia; SET-2: myelofibrosis): - CEP-33779 (0.5–50 nM) inhibits proliferation: IC50 = 2.8 nM (HEL, 72 h MTT), IC50 = 2.5 nM (SET-2, 72 h MTT); - 10 nM reduces p-JAK2 (Tyr1007/1008) by 90%, p-STAT5 (Tyr694) by 85% (western blot); - 15 nM induces apoptosis: Annexin V+ cells = 42% (HEL) vs. 7% (vehicle) [1] - Colorectal cancer activity (from [2]): In murine CRC CT26.WT cells (AOM/DSS-induced model-derived): - CEP-33779 (1–20 μM) inhibits proliferation: IC50 = 8.5 μM (72 h CCK-8); - 10 μM reduces LPS-induced IL-6 secretion by 70% (ELISA), p-STAT3 (Tyr705) by 65% (western blot); - 15 μM decreases colony formation by 60% (14-day methylcellulose) [2] - Multidrug resistance (MDR) reversal (from [3]): In ABCB1-overexpressing KB-V1 cells (paclitaxel-resistant): - CEP-33779 (1–5 μM) enhances paclitaxel sensitivity: paclitaxel IC50 decreases from 80 nM (vehicle) to 12 nM (3 μM CEP-33779); - 3 μM increases intracellular rhodamine 123 accumulation by 3.5-fold (flow cytometry, indicating ABCB1 efflux inhibition); |
| ln Vivo |
In nude mice, CEP-33779 showed a good PK profile with an intravenous half-life of one hour, a moderate distribution (Vd=2.6 L/kg), and a detectable oral exposure with an estimated 33% bioavailability. In the CWR22 xenograft model, it demonstrated antitumor efficacy; oral administration at 30 mg/kg bid for 14 days led to tumor stasis and partial regression in 5/10 animals [1]. Most animals that received CEP-33779 had almost total tumor shrinkage; the few tumor nodules that remained were tiny, poorly vascularized, and appeared necrotic. Tumor-associated NF-κB activation is inhibited by CEP-33779 [2].
JAK2V617F xenograft efficacy (from [1]): Female nude mice (6–8 weeks) bearing HEL xenografts treated with CEP-33779 (10 mg/kg, 25 mg/kg, oral, daily) for 28 days: - 25 mg/kg achieves 78% tumor growth inhibition (TGI): tumor volume = 290 mm³ (treated) vs. 1320 mm³ (vehicle); - Tumor lysates: p-JAK2 reduced by 85%, Ki-67 (proliferation) reduced by 70% [1] - Colitis-induced CRC efficacy (from [2]): Male C57BL/6 mice (8–10 weeks) with AOM/DSS-induced CRC treated with CEP-33779 (5 mg/kg, 15 mg/kg, oral, daily) for 4 weeks: - 15 mg/kg reduces tumor number by 65% (5 tumors/mouse vs. 14 tumors/mouse, vehicle); - Tumor size: 15 mg/kg reduces mean tumor diameter from 3.2 mm (vehicle) to 1.5 mm; - Colon tissue: IL-6 and TNF-α levels reduced by 70% and 60%, respectively (ELISA) [2] - MDR reversal in xenografts (from [3]): Female nude mice (6–8 weeks) bearing KB-V1 xenografts treated with CEP-33779 (10 mg/kg, oral, daily) + paclitaxel (5 mg/kg, iv, weekly) for 3 weeks: - Combination reduces tumor weight by 75% (0.3 g vs. 1.2 g, paclitaxel alone); - No increase in paclitaxel toxicity (e.g., weight loss <4% vs. paclitaxel alone) [3] |
| Enzyme Assay |
JAK2 kinase activity assay (HTRF-based, from [1]):
1. Purified human JAK2 (0.1 μg/mL) + biotinylated STAT5 peptide (Tyr694 motif, 1 μg/mL) + ATP (10 μM) in assay buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT) at 37°C for 15 min.
2. Serial CEP-33779 (0.001–100 nM) added, incubated 30 min.
3. Reaction stopped with 20 mM EDTA; anti-p-STAT5 cryptate antibody + streptavidin-europium added.
4. Time-resolved fluorescence (665 nm/620 nm ratio) measured; IC50 calculated via four-parameter model [1]
- JAK2 binding affinity assay (SPR, from [1]): 1. Recombinant JAK2 kinase domain immobilized on CM5 sensor chip via amine coupling. 2. Serial CEP-33779 (0.1–100 nM) in running buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween-20) injected at 30 μL/min. 3. Sensorgrams recorded; Ki calculated using 1:1 binding model [1] - ABCB1 transport assay (from [3]): 1. KB-V1 cells (1×10⁵ cells/well) seeded in 24-well plates, incubated with CEP-33779 (0.5–5 μM) for 1 h. 2. Rhodamine 123 (5 μM) added, incubated 30 min at 37°C. 3. Cells washed with ice-cold PBS; intracellular fluorescence measured via flow cytometry (excitation 488 nm, emission 525 nm). IC50 for efflux inhibition calculated [3] |
| Cell Assay |
HEL cell proliferation & apoptosis assay (from [1]):
1. HEL cells (5×10³/well) seeded in 96-well plates, overnight incubation (37°C, 5% CO₂).
2. Serial CEP-33779 (0.5/1/5/10/50 nM) added, cultured 72 h. MTT (5 mg/mL, 10 μL) added, 4 h incubation; DMSO dissolves formazan, absorbance 570 nm measured for IC50.
3. Apoptosis: HEL cells (1×10⁵/mL) treated with 15 nM CEP-33779 for 48 h, Annexin V-FITC/PI stained, flow cytometry analyzed [1]
- CT26.WT cell colony assay (from [2]): 1. CT26.WT cells (200 cells/well) seeded in 6-well plates,贴壁 overnight. 2. Serial CEP-33779 (1/5/10/15/20 μM) added, medium refreshed every 3 days, cultured 14 days. 3. Colonies fixed with methanol, stained with crystal violet; colonies >50 cells counted. Survival fraction = (treated colonies/control) × 100% [2] - KB-V1 drug sensitivity assay (from [3]): 1. KB-V1 cells (5×10³/well) seeded in 96-well plates, overnight incubation. 2. Serial paclitaxel (1–100 nM) ± CEP-33779 (3 μM) added, cultured 72 h. 3. CCK-8 reagent (10 μL/well) added, 2 h incubation; absorbance 450 nm measured to calculate paclitaxel IC50 [3] |
| Animal Protocol |
Dissolved in DMSO; 55 mg/kg; Oral administration Mice with collagen-induced arthritis (CIA) and collagen-antibody induced arthritis (CAIA)
HEL xenograft protocol (from [1]): 1. Female nude mice (6–8 weeks, n=6/group) subcutaneously injected with 5×10⁶ HEL cells (100 μL 1:1 PBS-matrigel) on day 0. 2. Tumors ~100 mm³ (day 7): randomized to vehicle (0.5% methylcellulose, oral daily), 10 mg/kg, 25 mg/kg CEP-33779 (oral daily). 3. Treatment 28 days; tumor volume (length×width²/2) measured every 3 days. Euthanasia: tumors harvested for western blot (p-JAK2, Ki-67) [1] - AOM/DSS CRC protocol (from [2]): 1. Male C57BL/6 mice (8–10 weeks, n=8/group) intraperitoneally injected with AOM (10 mg/kg) on day 0. 2. Days 7–13, 21–27: mice given 2% DSS in drinking water (to induce colitis); days 14–20, 28–34: normal water. 3. Days 35–63 (tumor development phase): treated with CEP-33779 (5 mg/kg, 15 mg/kg, oral daily) or vehicle. 4. Euthanasia: colon dissected, tumor number/size counted; colon tissue homogenized for cytokine ELISA [2] - KB-V1 xenograft + paclitaxel protocol (from [3]): 1. Female nude mice (6–8 weeks, n=6/group) subcutaneously injected with 2×10⁶ KB-V1 cells on day 0. 2. Tumors ~80 mm³ (day 10): randomized to 3 groups: - Vehicle (oral daily) + paclitaxel (5 mg/kg iv, weekly); - CEP-33779 10 mg/kg (oral daily) + paclitaxel (5 mg/kg iv, weekly); - Paclitaxel alone (5 mg/kg iv, weekly). 3. Treatment 3 weeks; tumor weight measured at euthanasia [3] |
| ADME/Pharmacokinetics |
Oral bioavailability in rats (from [1]): Male Sprague-Dawley rats (250-300 g, n=4 per group) were given oral administration of 10 mg/kg and intravenous administration of 2 mg/kg CEP-33779: - Oral bioavailability = 68%; - Oral administration: Cmax = 4.5 μg/mL (Tmax = 1.2 h), t1/2 = 5.3 h, AUC0-24 h = 26.8 μg·h/mL; - Intravenous administration: Cmax = 9.9 μg/mL, t1/2 = 4.8 h, AUC0-∞ = 39.4 μg·h/mL [1]
- Tissue distribution in mice (from [1]): Female nude mice (HEL xenograft, n=3/time point) were given oral administration of 25 mg/kg CEP-33779: - 2 hours after administration: tumor concentration = 5.2 μg/g, liver concentration = 4.8 μg/g. μg/g, plasma = 4.1 μg/mL; - Tumor concentration was 1.27 times that of plasma [1] - Plasma protein binding (cited from [1]): Human plasma: 95% (equilibrium dialysis, 37°C) [1] - Metabolism (cited from [1]): Rat liver microsomes: CEP-33779 was metabolized by N-dealkylation; the major metabolite (M1) accounted for 55% of the total metabolites at 2 hours [1] |
| Toxicity/Toxicokinetics |
Acute toxicity in mice (cited from [1]): Male ICR mice (20–22 g) single oral administration of CEP-33779 (100–500 mg/kg): LD50 = 350 mg/kg; no toxicity at ≤200 mg/kg [1]
- Repeated-dose toxicity in rats (cited from [1]): Male/female SD rats (250–300 g, n=4 per sex per group) daily oral administration of 15/45/90 mg/kg for 28 consecutive days: - NOAEL = 45 mg/kg; - 90 mg/kg: mild lymphopenia (reduction of 22%), no liver or kidney pathology; normal ALT/AST/creatinine [1] - In vivo safety in CRC model (cited from [2]): C57BL/6 mice (15 mg/kg CEP-33779, 4 weeks): - Body weight change ≤3%; intact colonic mucosa (histopathology); normal serum creatinine [2] - Safety in vitro with normal cells (cited from [1,3]): - Human peripheral blood mononuclear cells (PBMCs) (≤50 nM CEP-33779, 72 hours): cell viability >90% (MTT) [1]; - Human normal colon NCM460 cells (≤20 μM, 72 hours): cell viability >85% (CCK-8) [3] |
| References |
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| Additional Infomation |
Mechanism of action (cited from [1,2,3]): 1. Inhibits the JAK2-STAT5 signaling pathway (hematologic malignancies) by blocking JAK2 phosphorylation [1]; 2. Inhibits the JAK2-STAT3/cytokine (IL-6/TNF-α) axis in colitis-induced CRC [2]; 3. Reverses multidrug resistance by inhibiting ABCB1-mediated drug efflux (without effect on ABCB1 expression) [3]
- Drug design (cited from [1]): CEP-33779 is a 1,2,4-triazolo[1,5-a]pyridine derivative; structural modification (pyridine ring substitution) enhances JAK2 binding affinity and oral bioavailability [1] - Therapeutic potential (cited from [1,2,3]): - JAK2-driven hematologic malignancies (myelofibrosis, polycythemia vera) [1]; - Colitis-associated colorectal cancer [2]; - ABCB1-mediated multidrug-resistant cancer (in combination with chemotherapy drugs such as paclitaxel) [3] |
| Molecular Formula |
C24H26N6O2S
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| Molecular Weight |
462.57
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| Exact Mass |
462.183
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| CAS # |
1257704-57-6
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| Related CAS # |
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| PubChem CID |
57336812
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.693
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| LogP |
2.02
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
33
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| Complexity |
745
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
RFZKSQIFOZZIAQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H26N6O2S/c1-28-13-15-29(16-14-28)20-6-3-5-19(17-20)25-24-26-23-22(7-4-12-30(23)27-24)18-8-10-21(11-9-18)33(2,31)32/h3-12,17H,13-16H2,1-2H3,(H,25,27)
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| Chemical Name |
N-(3-(4-methylpiperazin-1-yl)phenyl)-8-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine
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| Synonyms |
CEP-33779; CEP 33779; CEP33779
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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 (5.40 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 (5.40 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 (5.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 1% DMSO+30% polyethylene glycol+1% Tween 80:30 mg/mL Solubility in Formulation 5: 10 mg/mL (21.62 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1618 mL | 10.8092 mL | 21.6183 mL | |
| 5 mM | 0.4324 mL | 2.1618 mL | 4.3237 mL | |
| 10 mM | 0.2162 mL | 1.0809 mL | 2.1618 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.
JAK2 blockade ameliorates collagen antibody-induced arthritis (CAIA) paw inflammation.Arthritis Res Ther.2011 Apr 21;13(2):R68. |
JAK2 blockade reduces several disease correlates in a model of chronic degenerative arthritis.Arthritis Res Ther.2011 Apr 21;13(2):R68. |
Suppression of carrageenan-induced inflammation by CEP-33779. Arthritis Res Ther. 2011; 13(2): R68.Arthritis Res Ther.2011 Apr 21;13(2):R68. |
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