CEP-33779JAK2 inhibitor,highly selective CAS# 1257704-57-6 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
| Cas No. | 1257704-57-6 | SDF | Download SDF |
| PubChem ID | 57336812 | Appearance | Powder |
| Formula | C24H26N6O2S | M.Wt | 462.57 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | Soluble in DMSO > 10 mM | ||
| Chemical Name | N-[3-(4-methylpiperazin-1-yl)phenyl]-8-(4-methylsulfonylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine | ||
| SMILES | CN1CCN(CC1)C2=CC(=CC=C2)NC3=NN4C=CC=C(C4=N3)C5=CC=C(C=C5)S(=O)(=O)C | ||
| Standard InChIKey | RFZKSQIFOZZIAQ-UHFFFAOYSA-N | ||
| Standard InChI | 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) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | CEP-33779 is a selective inhibitor of JAK2 with IC50 value of 1.8 nM. | |||||
| Targets | JAK2 | |||||
| IC50 | 1.8 nM | |||||
CEP-33779 Dilution Calculator
CEP-33779 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.1618 mL | 10.8092 mL | 21.6183 mL | 43.2367 mL | 54.0459 mL |
| 5 mM | 0.4324 mL | 2.1618 mL | 4.3237 mL | 8.6473 mL | 10.8092 mL |
| 10 mM | 0.2162 mL | 1.0809 mL | 2.1618 mL | 4.3237 mL | 5.4046 mL |
| 50 mM | 0.0432 mL | 0.2162 mL | 0.4324 mL | 0.8647 mL | 1.0809 mL |
| 100 mM | 0.0216 mL | 0.1081 mL | 0.2162 mL | 0.4324 mL | 0.5405 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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CEP-33779, is a highly selective, orally active inhibitor of Janus kinase 2 (JAK2). When evaluate against the other members of the JAK family, CEP-33779 demonstrates varying degrees of selectivity from >40-fold versus JAK1 to >800-fold against TYK2. In a cellular system, CEP-33779 is shown to inhibit JAK2 in irf-bla TF-1 cells utilizing the GeneBLAzer reporter assay. It is also able to mitigate several immune parameters associated with SLE advancement, including the protection and treatment of mice with lupus nephritis. 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.
Reference
Kristine L Stump, Lily D Lu, Pawel Dobrzanski, Cynthia Serdikoff, Diane E Gingrich, Ben J Dugan, Thelma S Angeles, Mark S Albom, Mark A Ator, Bruce D Dorsey, Bruce A Ruggeri, Matthew M Seavey. A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis. Arthritis Research & Therapy 2011, 13:R68.
Lily D. Lu, Kristine L. Stump, Nate H. Wallace, Pawel Dobrzanski, Cynthia Serdikoff, Diane E. Gingrich, Benjamin J. Dugan, Thelma S. Angeles, Mark S. Albom, Jennifer L. Mason, Mark A. Ator, Bruce D. Dorsey, Bruce A. Ruggeri, Matthew M. Seavey. Depletion of Autoreactive Plasma Cells and Treatment of Lupus Nephritis in Mice Using CEP-33779, a Novel, Orally Active, Selective Inhibitor of JAK2. The Journal of Immunology October 1, 2011 vol. 187 no. 7 3840-3853.
Matthew M. Seavey, Lily D. Lu, Kristine L. Stump, Nate H. Wallace, William Hockeimer, Teresa M. O'Kane, Bruce A. Ruggeri, Pawel Dobrzanski. Therapeutic Efficacy of CEP-33779, a Novel Selective JAK2 Inhibitor, in a Mouse Model of Colitis-Induced Colorectal Cancer. Mol Cancer Ther April 2012 11; 984.
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A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: discovery of CEP-33779.[Pubmed:22594690]
J Med Chem. 2012 Jun 14;55(11):5243-54.
Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure-activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2.
Depletion of autoreactive plasma cells and treatment of lupus nephritis in mice using CEP-33779, a novel, orally active, selective inhibitor of JAK2.[Pubmed:21880982]
J Immunol. 2011 Oct 1;187(7):3840-53.
Accumulating evidence suggests that autoreactive plasma cells play an important role in systemic lupus erythematosus (SLE). In addition, several proinflammatory cytokines promote autoreactive B cell maturation and autoantibody production. Hence, therapeutic targeting of such cytokine pathways using a selective JAK2 inhibitor, CEP-33779 (JAK2 enzyme IC(50) = 1.3 nM; JAK3 enzyme IC(50)/JAK2 enzyme IC(50) = 65-fold), was tested in two mouse models of SLE. Age-matched, MRL/lpr or BWF1 mice with established SLE or lupus nephritis, respectively, were treated orally with CEP-33779 at 30 mg/kg (MRL/lpr), 55 mg/kg or 100 mg/kg (MRL/lpr and BWF1). Studies included reference standard, dexamethasone (1.5 mg/kg; MRL/lpr), and cyclophosphamide (50 mg/kg; MRL/lpr and BWF1). Treatment with CEP-33779 extended survival and reduced splenomegaly/lymphomegaly. Several serum cytokines were significantly decreased upon treatment including IL-12, IL-17A, IFN-alpha, IL-1beta, and TNF-alpha. Anti-nuclear Abs and frequencies of autoantigen-specific, Ab-secreting cells declined upon CEP-33779 treatment. Increased serum complement levels were associated with reduced renal JAK2 activity, histopathology, and spleen CD138(+) plasma cells. The selective JAK2 inhibitor CEP-33779 was able to mitigate several immune parameters associated with SLE advancement, including the protection and treatment of mice with lupus nephritis. These data support the possibility of using potent, orally active, small-molecule inhibitors of JAK2 to treat the debilitative disease SLE.
Therapeutic efficacy of CEP-33779, a novel selective JAK2 inhibitor, in a mouse model of colitis-induced colorectal cancer.[Pubmed:22334590]
Mol Cancer Ther. 2012 Apr;11(4):984-93.
Constitutively activated STAT3 and STAT5 are expressed in a wide variety of human malignancies including solid and hematopoietic cancers and often correlate with a poor prognosis and resistance to multiple therapies. Given the well established role of STAT3 in tumorigenesis, inhibition of Janus-activated kinase 2 (JAK2) activity might represent an attractive therapeutic approach. Using a mouse model of colitis-induced colorectal cancer, we show that a novel, orally active, selective JAK2 inhibitor, CEP-33779, induced regression of established colorectal tumors, reduced angiogenesis, and reduced proliferation of tumor cells. Histopathologic analysis confirmed reduced incidence of histologic-grade neoplasia by CEP-33779. Tumor regression correlated with inhibition of STAT3 and NF-kappaB (RelA/p65) activation in a CEP-33779 dose-dependent manner. In addition, the expression of proinflammatory, tumor-promoting cytokines interleukin (IL)-6 and IL-1beta was strongly reduced upon JAK2 inhibition. 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.
CEP-33779 antagonizes ATP-binding cassette subfamily B member 1 mediated multidrug resistance by inhibiting its transport function.[Pubmed:25058526]
Biochem Pharmacol. 2014 Sep 15;91(2):144-56.
The overexpression of ATP-binding cassette (ABC) transporters often leads to the development of multidrug resistance (MDR), which is the major factor contributing to the failure of chemotherapy. The objective of this study was to investigate the enhancement of CEP-33779, a small-molecule inhibitor of Janus kinase 2 (JAK2), on the efficacy of conventional chemotherapeutic agents in MDR cells with overexpression of P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2). Our results showed that CEP-33779, at nontoxic concentrations, significantly sensitized ABCB1 overexpressing MDR cells to its anticancer substrates. CEP-33779 significantly increased intracellular accumulation and decreased the efflux of doxorubicin by inhibiting the ABCB1 transport function. Furthermore, CEP-33779 did not alter the expression of ABCB1 both at protein and mRNA levels but did stimulate the activity of ABCB1 ATPase. CEP-33779 was predicted to bind within the large hydrophobic cavity of homology modeled ABCB1. In addition, the down-regulation of JAK2 by shRNA altered neither the expression of ABCB1 nor the cytotoxic effect of chemotherapeutic agents in ABCB1-overexpressing cells. Significantly, CEP-33779 enhanced the efficacy of vincristine against the ABCB1-overexpressing and drug resistant KBv200 cell xenograft in nude mice. In conclusion, we conclude that CEP-33779 enhances the efficacy of substrate drugs in ABCB1-overexpressing cells by directly inhibiting ABCB1 transport function. The findings encouraged to further study on the combination therapy of CEP-33779 with conventional chemotherapeutic agents in ABCB1 mediated-MDR cancer patients.
