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Cerdulatinib

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Chemical Structure| 1198300-79-6 同义名 : PRT062070;PRT2070
CAS号 : 1198300-79-6
货号 : A137124
分子式 : C20H27N7O3S
纯度 : 99%+
分子量 : 445.538
MDL号 : N/A
存储条件：

粉末 Keep in dark place,Inert atmosphere,Room temperature

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 30 mg/mL(67.33 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • JAK1

    JAK1, IC50:12 nM

  • JAK3

    JAK3, IC50:8 nM

  • Tyk2

    TYK2, IC50:0.5 nM

  • JAK2

    JAK2, IC50:6 nM
描述 The JAK/STAT pathway forms a critical node affecting multiple signaling pathways in both the innate and adaptive immune responses. JAK family members include Janus kinases 1, 2, and 3 (JAK1, JAK2, and JAK3, respectively) and tyrosine kinase 2 (TYK2). JAK1 and JAK2 and TYK2 are broadly activated by different cytokines across cell types, while JAK3 is limited to primarily hematopoietic cells. Cerdulatinib/PRT-062070 is an orally active nonspecific kinase inhibitor with an IC50 of 0.5, 12, 6, or 8 nM for TYK2, JAK1, JAK2, or JAK3, respectively. At the cellular level, cerdulatinib demonstrates specificity towards JAK1/JAK3 and TYK2, but not JAK2-mediated responses and it is currently in phase 1/2A clinical trials for CLL (chronic lymphocytic leukemia) as well as other B-cell Non Hodgkin lymphomas, with first in man clinical trial data and therapeutic responses in patients resistant to ibrutinib already reported. The specificity of cerdulatinib was also demonstrated by its lack of inhibition of T cell receptor signaling or protein kinase C signaling in whole blood[3]. On a tissue microarray of 62 primary DLBCL (large B-cell lymphoma) tumors with 58% expressed either phosphorylated SYK or STAT3 or both. Cerdulatinib induced DLBCL cells apoptosis which was associated with caspase-3 and PARP cleavage with IC50 of 32 nM and 12 nM for SYK and JAK1[4]. PBMCs from CLL patients were treated with cerdulatinib ranging from 0-1μM. Cerdulatinib induced apoptosis of CLL cells in a time- and concentration-dependent manner, and particularly in IGHV unmutated samples with greater BCR-signaling capacity and response to IL-4, which showed that Cerdulatinib is a promising therapeutic for the treatment of CLL either alone or in combination with venetoclax[5].
作用机制 The functional groups that interact with Leu377, Gly378, and Val385 in the G-loop and the nearby region in SYK (Spleen tyrosine kinase) can bind to the enzyme pocket.
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.24mL

0.45mL

0.22mL

11.22mL

2.24mL

1.12mL

22.44mL

4.49mL

2.24mL
参考文献

[1]Guo A, Lu P, Coffey G, 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, Betz A, 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.

[3]Juillerat-Jeanneret L, Aubert JD, Mikulic J, Golshayan D. Fibrogenic Disorders in Human Diseases: From Inflammation to Organ Dysfunction. J Med Chem. 2018 Nov 21;61(22):9811-9840. doi: 10.1021/acs.jmedchem.8b00294. Epub 2018 Jul 17. PMID: 29969256.

[4]Ma J, Xing W, Coffey G, Dresser K, Lu K, Guo A, Raca G, Pandey A, Conley P, Yu H, Wang YL. 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 Dec 22;6(41):43881-96. doi: 10.18632/oncotarget.6316. PMID: 26575169; PMCID: PMC4791274.

[5]Blunt MD, Koehrer S, Dobson RC, Larrayoz M, Wilmore S, Hayman A, Parnell J, Smith LD, Davies A, Johnson PWM, Conley PB, Pandey A, Strefford JC, Stevenson FK, Packham G, Forconi F, Coffey GP, Burger JA, Steele AJ. The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia. Clin Cancer Res. 2017 May 1;23(9):2313-2324. doi: 10.1158/1078-0432.CCR-16-1662. Epub 2016 Oct 3. PMID: 27697994; PMCID: PMC5417366.