Cerdulatinib (PRT062070)Syk/JAK inhibitor CAS# 1198300-79-6 |
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| Cas No. | 1198300-79-6 | SDF | Download SDF |
| PubChem ID | 44595079 | Appearance | Powder |
| Formula | C20H27N7O3S | M.Wt | 445.54 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | PRT062070; PRT2070 | ||
| Solubility | DMSO : ≥ 30 mg/mL (67.33 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide | ||
| SMILES | CCS(=O)(=O)N1CCN(CC1)C2=CC=C(C=C2)NC3=NC=C(C(=N3)NC4CC4)C(=O)N | ||
| Standard InChIKey | BGLPECHZZQDNCD-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C20H27N7O3S/c1-2-31(29,30)27-11-9-26(10-12-27)16-7-5-15(6-8-16)24-20-22-13-17(18(21)28)19(25-20)23-14-3-4-14/h5-8,13-14H,2-4,9-12H2,1H3,(H2,21,28)(H2,22,23,24,25) | ||
| 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 | Cerdulatinib is a novel, orally available, ATP-competitive JAK and SYK inhibitor that demonstrates selective inhibition of TYK2 and SYK with an IC50 of 0.5 nM and 32 nM.In Vitro:Cerdulatinib shows inhibitory effect on 60 CLL with IC50 ranging from 0.37 to 10.02 µM. Cerdulatinib induces apoptosis in CLL in association with MCL-1 down-regulation and PARP cleavage. Cerdulatinib (2μM) is able to overcome the support of the microenvironment and induces CLL cell death. Cerdulatinib (250-500 nM) blocks proliferation of ibrutinib-sensitive and ibrutinib-resistant primary CLL cells. Cerdulatinib also blocks proliferation of both ibrutinib-sensitive and ibrutinib-resistant primary CLL cells as well as BTKC481S-transfected cell lines, and blocks BCR and JAK-STAT signaling pathways. Furthermore, inhibition of SYK and JAK by cerdulatinib translates to downstream inhibition of AKT and ERK. Cerdulatinib inhibits the activity of NF-kB pathway[1]. PRT062070 reduces the ability of stimulated B cells to upregulate cell-surface expression of the early activation marker CD69 (IC50=0.11 µM). PRT062070 exhibits differential potency against cytokine JAK/STAT signaling pathways. PRT062070 (1 or 3 µM) induces apoptosis in BCR-signaling competent NHL cell lines[2]. Cerdulatinib demonstrates inhibitory activity against both ABC and GCB subtypes of DLBCL cells. Cerdulatinib also induces apoptosis in both GCB and ABC subtypes of DLBCL cell lines via caspase 3 and PARP cleavage. And cerdulatinib blocks cell cycle in both ABC and GCB subtypes of DLBCL via inhibition of RB phosphorylation and down-regulation of cyclin E. Cerdulatinib induces cell cycle arrest and apoptosis under the condition of BCR stimulation in all DLBCL cell lines. Besides, cerdulatinib blocks JAK/STAT and BCR signaling in both ABC and GCB DLBCL cell lines. Cerdulatinib induces cell death in primary human DLBCL samples[3]. Cerdulatinib inhibits BCR-induced signals in a dose-dependent manner and most strongly between 0.3 to 1 μM. and particularly in IGHV-unmutated samples with greater BCR signaling capacity and response to IL4, or samples expressing higher levels of sIgM, CD49d+, or ZAP70+. Cerdulatinib overcomes anti-IgM, IL4/CD40L, or NLC-mediated protection by preventing upregulation of MCL-1 and BCL-XL; however, BCL-2 expression is unaffected. Furthermore, in samples treated with IL4/CD40L, cerdulatinib synergizes with venetoclax in vitro to induce greater apoptosis than either drug alone[4].In Vivo:PRT062070 (0.5 mg/kg) results in a nonstatistically significant trend toward reduced ankle inflammation, whereas significant reductions in inflammation are achieved with the 1.5, 3, and 5 mg/kg doses. PRT062070 also affects anticollagen antibody formation. PRT062070 (15 mg/kg) suppresses upregulation of splenic B-cell surface CD80/86 and CD69, and inhibits BCR signaling and activation in the spleen after oral dosing in mice[2]. References: | |||||
| Cell experiment [1]: | |
| Cell lines | DLBCL (diffuse large B-cell lymphoma) cells: germinal center B-cell (GCB) subtype, activated B-cell (ABC) subtype. |
| Preparation method | Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
| Reacting condition | 6 h |
| Applications | Cerdulatinib induces apoptosis in both GCB and ABC cell lines by caspase 3 and PARP cleavage. Cerdulatinib also triggers apoptosis and cell cycle arrest in BCR-stimulated DLBCL cells. Cerdulatinib blocks JAK/STAT and BCR signaling in both ABC and GCB cell lines as well. |
| Animal experiment [2]: | |
| Animal models | Female Lewis rats collagen-induced arthritis (CIA) model |
| Dosage form | Oral gavage twice daily. |
| Application | 3 mg/kg of Cerdulatinib suppresses the inflammation and reverses relative to pretreatment levels at 5 mg/kg. Cerdulatinib also dose-dependently leads to significant improvements in inflammatory infiltrate within the synovium and the integrity of the articular cartilage. Moreover, Cerdulatinib treatment affects anticollagen antibody formation and reduces 50% of circulating antibody titers at the 1.5, 3, and 5 mg/kg doses. |
| Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
| References: 1. Ma J, Xing W, Coffey G et al. Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma. Oncotarget. 2015 Nov 5. 2. Coffey G, Betz A, DeGuzman F et al.The novel kinase inhibitor PRT062070 (Cerdulatinib)demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther. 2014 Dec;351(3):538-48. | |
Cerdulatinib (PRT062070) Dilution Calculator
Cerdulatinib (PRT062070) Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.2445 mL | 11.2223 mL | 22.4447 mL | 44.8893 mL | 56.1117 mL |
| 5 mM | 0.4489 mL | 2.2445 mL | 4.4889 mL | 8.9779 mL | 11.2223 mL |
| 10 mM | 0.2244 mL | 1.1222 mL | 2.2445 mL | 4.4889 mL | 5.6112 mL |
| 50 mM | 0.0449 mL | 0.2244 mL | 0.4489 mL | 0.8978 mL | 1.1222 mL |
| 100 mM | 0.0224 mL | 0.1122 mL | 0.2244 mL | 0.4489 mL | 0.5611 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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Cerdulatinib (PRT062070) is a potent and selective inhibitor of Syk and JAK.[1]
The JAK/STAT cascade, which has been implicated in hematopoiesis and cytokine signaling, is present in humans and flies. Worms. The SYK/ZAP70 kinases play an important role in human T and B cell signaling.[3]
Cerdulatinib can induce apoptosis via down-regulation of MCL1 protein and PARP cleavage. Through the inhibition of RB phosphorylation and down-regulation of cyclin E,the Cerdulatinib can also block G1/S transition and cause cell cycle arrest. Further analyses of the cell signaling activities showed that STAT3 phosphorylation was sensitive to inhibition by cerdulatinib in ABC cell lines while phosphorylation of SYK, PLCg2, AKT and ERK is reported to be sensitive to inhibition by cerdulatinib in GCB cell lines.[2]
Cerdulatinib is effective in rodent models of B-cell lymphoma and autoimmune disease and has exhibited anti-tumor activity in genetically diverse B-cell lymphoma cell lines and is more effective than Syk- or Jak- selective inhibitors alone.[1]
References:
[1] Manish Patel , Pau Hamlin, MD, etal. , A Phase I Open-Label, Multi-Dose Escalation Study of the Dual Syk/Jak Inhibitor PRT062070 (Cerdulatinib) in Patients with Relapsed/Refractory B Cell Malignancies. Blood: 124 (21) ; December 6, 2014.
[2] Y. Lynn Wang, MD PhD, Jiao Ma, PhD, etal., SYK and STAT3 Are Active in Diffuse Large B-Cell Lymphoma: Activity of Cerdulatinib, a Dual SYK/JAK Inhibitor. Blood: 124 (21) ; December 6, 2014.
[3]Morrison DK, Murakami MS, Cleghon V. Protein kinases and phosphatases in the Drosophila genome. J Cell Biol. 2000 Jul 24;150(2):F57-62.
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The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer.[Pubmed:25253883]
J Pharmacol Exp Ther. 2014 Dec;351(3):538-48.
The heterogeneity and severity of certain autoimmune diseases and B-cell malignancies warrant simultaneous targeting of multiple disease-relevant signaling pathways. Dual inhibition of spleen tyrosine kinase (SYK) and Janus kinase (JAK) represents such a strategy and may elicit several benefits relative to selective kinase inhibition, such as gaining control over a broader array of disease etiologies, reducing probability of selection for bypass disease mechanisms, and the potential that an overall lower level suppression of individual targets may be sufficient to modulate disease activity. To this end, we provide data on the discovery and preclinical development of PRT062070 [4-(cyclopropylamino)-2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimid ine-5-carboxamide hydrochloride], an orally active kinase inhibitor that demonstrates activity against SYK and JAK. Cellular assays demonstrated specific inhibitory activity against signaling pathways that use SYK and JAK1/3. Limited inhibition of JAK2 was observed, and PRT062070 did not inhibit phorbol 12-myristate 13-acetate-mediated signaling or activation in B and T cells nor T-cell antigen receptor-mediated signaling in T cells, providing evidence for selectivity of action. Potent antitumor activity was observed in a subset of B-cell lymphoma cell lines. After oral dosing, PRT062070 suppressed inflammation and autoantibody generation in a rat collagen-induced arthritis model and blocked B-cell activation and splenomegaly in a mouse model of chronic B-cell antigen receptor stimulation. PRT062070 is currently under evaluation in a phase I dose escalation study in patients with B-cell leukemia and lymphoma (NCT01994382), with proof-of-concept studies in humans planned to assess therapeutic potential in autoimmune and malignant diseases.
