1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemECerdulatinibCat. No.: HY-15999CAS No.: 1198300-79-6Synonyms: PRT062070; PRT2070分式: CHNOS分量: 445.54作靶點(diǎn): JAK; Syk作通路: Epigenetics; JAK/STAT Signaling; Stem Cell/Wnt; ProteinTyrosine Kinase/RTK儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn s

2、olvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 30 mg/mL (67.33 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲(chǔ)備液1 mM 2.2445 mL 11.2223 mL 22.4447 mL5 mM 0.4489 mL 2.2445 mL 4.4889 mL10 mM 0.2244 mL 1.1222 mL 2.2445 mL請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲(chǔ)備液，并請(qǐng)注意儲(chǔ)備液的保存式和

3、期限。BIOLOGICAL ACTIVITY物活性 Cerdulatinib (PRT062070)是JAK 和 SYK 的雙抑制劑，抑制JAK1，2，3 和SYK的 IC50 分別為12，6，8 和32。IC50 & Target Tyk2 JAK2 JAK3 JAK11/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE0.5 nM (IC50) 6 nM (IC50) 8 nM (IC50) 12 nM (IC50)Syk MST1 ARK5 MLK132 nM (IC50) 4 nM (IC50) 4 nM (IC50) 5 nM (IC50

4、)FMS AMPK TBK1 MARK15 nM (IC50) 6 nM (IC50) 10 nM (IC50) 10 nM (IC50)PAR1B-a TSSK MST2 GCK13 nM (IC50) 14 nM (IC50) 15 nM (IC50) 18 nM (IC50)JNK3 Rsk2 Rsk4 CHK118 nM (IC50) 20 nM (IC50) 28 nM (IC50) 42 nM (IC50)Flt4 Flt3 Ret Itk51 nM (IC50) 90 nM (IC50) 105 nM (IC50) 194 nM (IC50)體外研究 Cerdulatinib s

5、hows inhibitory effect on 60 CLL with IC50 ranging from 0.37 to 10.02 M. Cerdulatinib inducesapoptosis in CLL in association with MCL-1 down-regulation and PARP cleavage. Cerdulatinib (2M) is ableto overcome the support of the microenvironment and induces CLL cell death. Cerdulatinib (250-500 nM)blo

6、cks proliferation of ibrutinib-sensitive and ibrutinib-resistant primary CLL cells. Cerdulatinib also blocksproliferation 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, inh

7、ibition of SYKand JAK by cerdulatinib translates to downstream inhibition of AKT and ERK. Cerdulatinib inhibits the activityof NF-kB pathway 1. PRT062070 reduces the ability of stimulated B cells to upregulate cell-surfaceexpression of the early activation marker CD69 (IC50=0.11 M). PRT062070 exhibi

8、ts differential potencyagainst cytokine JAK/STAT signaling pathways. PRT062070 (1 or 3 M) induces apoptosis in BCR-signalingcompetent NHL cell lines 2. Cerdulatinib demonstrates inhibitory activity against both ABC and GCBsubtypes of DLBCL cells. Cerdulatinib also induces apoptosis in both GCB and A

9、BC subtypes of DLBCL celllines via caspase 3 and PARP cleavage. And cerdulatinib blocks cell cycle in both ABC and GCB subtypes ofDLBCL via inhibition of RB phosphorylation and down-regulation of cyclin E. Cerdulatinib induces cell cyclearrest and apoptosis under the condition of BCR stimulation in

10、all DLBCL cell lines. Besides, cerdulatinibblocks JAK/STAT and BCR signaling in both ABC and GCB DLBCL cell lines. Cerdulatinib induces cell deathin primary human DLBCL samples 3. Cerdulatinib inhibits BCR-induced signals in a dose-dependentmanner and most strongly between 0.3 to 1 M. and particular

11、ly in IGHV-unmutated samples with greaterBCR signaling capacity and response to IL4, or samples expressing higher levels of sIgM, CD49d+, orZAP70+. Cerdulatinib overcomes anti-IgM, IL4/CD40L, or NLC-mediated protection by preventingupregulation of MCL-1 and BCL-XL; however, BCL-2 expression is unaff

12、ected. Furthermore, in samplestreated with IL4/CD40L, cerdulatinib synergizes with venetoclax in vitro to induce greater apoptosis thaneither drug alone 4.體內(nèi)研究PRT062070 (0.5 mg/kg) results in a nonstatistically significant trend toward reduced ankle inflammation,whereas significant reductions in inf

13、lammation are achieved with the 1.5, 3, and 5 mg/kg doses. PRT062070also affects anticollagen antibody formation. PRT062070 (15 mg/kg) suppresses upregulation of splenic B-2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEcell surface CD80/86 and CD69, and inhibits BCR signaling and activation in the

14、 spleen after oral dosing inmice 2.PROTOCOLCell Assay 1 TMD8 cells are transfected with constructs of WT BTK or BTKC481S mutants using kit V, Program U-13 onAmaxa Nucleofector. After transfection, the cells are co-cultured with NKTert cells in a 24-well plate for 24hrs for recovery. Ibrutinib, cerdu

15、latinib and vehicle (DMSO) are then added into the transfected TMD8 cellsand cellular viability is determined with MuseTM Count & Viability kit using Muse Cell Analyzer. The cellsurvival is determined by flow cytometry using the Annexin V/7-AAD Apoptosis Detection Kit I on freshlyisolated CLL cells.

16、MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Science. 2017 Dec 1;358(6367). ImmunoHorizons. 2019 May. Patent. US20180263995A1. Methods Mol Biol. 2018;1711:351-398.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Guo A

17、, et al. Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib,induces apoptosis of tumor cells protected by the microenvironment. Oncotarget. 2017 Feb 21;8(8):12953-12967.2. Coffey G, et al. The novel kinase inhibitor PRT062070 (Cerd

18、ulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer.J Pharmacol Exp Ther. 2014 Dec;351(3):538-48.3. Ma J, et al. Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuselarge B cell lymphoma. Oncotarget. 2015 Dec 22;6(41):43881-96.4. Blunt MD, et al. The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signali