AZD1480JAK2 inhibitor,ATP-competitive and novel |
Sample solution is provided at 25 µL, 10mM.
Quality Control & MSDS
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- Purity = 98.01%
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Chemical structure
Description | AZD1480 is an ATP-competitive inhibitor of JAK2 with IC50 value of 0.26 nM. | |||||
Targets | JAK2 | |||||
IC50 | 0.26 nM |
Cell experiment: [1] | |
Cell lines | SKOV3 cells |
Preparation method | The solubility of this compound in DMSO is >93.8mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
Reaction Conditions | 10 μM, 24 hours |
Applications | In the AZD1480 combined with cisplatin treatment groups, cisplatin could inhibit the proliferation of SKOV3 cells with dose dependent (P<0.05).there was="" no="" significant="" difference="" between="" 1="" μmol/l="" azd1480="" group="" and="" control="" group="" (p="">0.05) butwas statistically significant difference 5 μmol/L and 10 μmol/L AZD148 groups compared with the control group (P<0.05). the="" coefficient="" ofdruginteraction="" (cdi)="" values="" were="" (0.902,="" 0.914,="" 0.95,="" 0.893,="" 0.848,="" 0.974,="" 0.923,0.767,="" 0.372)="">0.05).><1, which="" confirmed="" that="" these="" two="" drugs="" were="" synergistic.="" cdi="" value="" was="" 0.372="" when="" the="" concentration="" was80μg/ml="" cisplatin="" +="" 10="" μmol/l="" azd1480,which="" showed="" that="" their="" synergistic="" effects="" were="" very="">1,> 0.05).there> |
Animal experiment: [2] | |
Animal models | SCID/Beige mice injected with TC32 or Rh18 cells |
Dosage form | Oral administration, 30 mg/kg, twice a day for 21 days |
Applications | The tumor growth in AZD1480-treated group was significantly depressed compared to control in each cell line. Tumors from mice treated with AZD1480 had decreased levels of tyrosine phosphorylated STAT3 as well as of STAT3 downstream targets (CyclinD1,-3, Bcl-2 and Survivin) compared to the levels in tumors from mice receiving vehicle. This shows that AZD1480 treatment induces the inhibition of STAT3 activity and its target gene expression in vivo. |
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] Xin Y L Y, Yang Y, Han P. AZD1480 can inhibit the biological behavior of ovarian cancer SKOV3 cells in vitro. Asian Pacific Journal of Cancer Prevention, 2013, 14(8): 4823-4827. [2] Yan S, Li Z, Thiele C J. Inhibition of STAT3 with orally active JAK inhibitor, AZD1480, decreases tumor growth in Neuroblastoma and Pediatric Sarcomas In vitro and In vivo. Oncotarget, 2013, 4(3): 433. |
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Cas No. | 935666-88-9 | SDF | Download SDF |
Synonyms | AZD 1480 | ||
Chemical Name | 5-chloro-2-N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-4-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine | ||
Canonical SMILES | CC1=CC(=NN1)NC2=NC(=NC=C2Cl)NC(C)C3=NC=C(C=N3)F | ||
Formula | C14H14ClFN8 | M.Wt | 348.77 |
Solubility | ≥93.8 mg/mL in DMSO, ≥4.57 mg/mL in EtOH with ultrasonic and warming, <2.56 mg/ml="" in="" h2o="">2.56> | Storage | Store at -20°C |
Shipping Condition | Evaluation sample solution : ship with blue ice.All other available size:ship with RT , or blue ice upon request | ||
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. |
AZD1480 is a novel small-molecule JAK inhibitor. It is able to block cell proliferation and induce apoptosis of myeloma cell lines. It can effectively inhibit tumor angiogenesis and metastasis mediated by STAT3 in stromal cells as well as tumor cells. AZD1480 has broad efficacy on a wider variety of myeloma cells, such as RPMI 8226, OPM-2, NCI-H929, Kms.18, MM1.S and IM-9, as well as primary myeloma cells. AZD1480 induces cell death of Kms.11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms.11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho-STAT3 and Cyclin D2 levels. AZD1480 also demonstrates important Jak2 selectivity over Jak3, in particular at high ATP concentrations and marginal selectivity over Jak1 at Km ATP.
Reference
A Scuto, P Krejci, L Popplewell, J Wu, Y Wang, M Kujawski, C Kowolik, H Xin, L Chen, Y Wang, L Kretzner, H Yu, W R Wilcox, Y Yen, S Forman and R Jove. The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia. 2011 March ; 25(3): 538–550
Michael Hedvat, Dennis Huszar, Andreas Herrmann, Joseph M. Gozgit, Anne Schroeder, Adam Sheehy, Ralf Buettner, David Proia, Claudia M. Kowolik, Hong Xin, Brian Armstrong, Geraldine Bebernitz, Shaobu Weng, Lin Wang, Minwei Ye, Kristen McEachern, Huawei Chen, Deborah Morosini, Kirsten Bell, Marat Alimzhanov, Stephanos Ioannidis, Patricia McCoon, Zhu A. Cao, Hua Yu, Richard Jove, Michael Zinda. The JAK2 Inhibitor AZD1480 Potently Blocks Stat3 Signaling and Oncogenesis in Solid Tumors. Cancer Cell. 2009; 16 (6): 487–497
Hong Xin, Andreas Herrmann, Karen Reckamp, Wang Zhang, Sumanta Pal, Michael Hedvat, Chunyan Zhang, Wei Liang, Anna Scuto, Shaobu Weng, Deborah Morosini, Zhu A. Cao, Michael Zinda, Robert Figlin, Dennis Huszar, Richard Jove, Hua Yu. Antiangiogenic and Antimetastatic Activity of JAK Inhibitor AZD1480. Cancer Research. 2011;71: 6601-6610
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生物膜的生物屏障作用阻止了许多高分子物质进入细胞内,然而穿透细胞膜进入细胞内是许多作用靶点在细胞内的生物大分子发挥作用的先决条件,,从而很大程度地限制了这些物质在治疗领域的应用。因此,如何引导这些物质穿透细胞膜是一个迫切需要解决的问题,目前介导生物大分子穿透细胞膜的方法主要包括细胞穿透肽(cellpenetratingpeptides,CPPs)、脂质体、腺病毒、纳米颗粒、影细胞等,而CPPs是一类以非受体依赖方式,非经典内吞方式直接穿过细胞膜进入细胞的多肽,它们的长度一般不超过30个氨基酸且富含碱性氨基酸,氨基酸序列通常带正电荷。
细胞穿透肽(cellpenetratingpeptides,CPPs)的一个重要特点是可以携带多种不同大小和性质的生物活性物质进入细胞,包括小分子化合物、染料、多肽、多肽核酸(peptidenucleoacid,PNA)、蛋白质、质粒DNA、siRNA、200nm的脂质体、噬菌体颗粒和超顺磁性粒子等,这一性质为其成为靶向药物的良好载体提供了可能。CPPs作为载体的优势在于低毒性和无细胞类型的限制,尽管CPPs可输送不同类型的物质进入细胞,但其实际应用多集中于寡肽、蛋白质、寡聚核苷(oligonucleotides,ONs)或类似物的细胞转运。
1型人免疫缺陷病毒转录激活因子TAT(humanimmunodeficiencyvirus-1transcriptionactivator,HIV-1TAT)是第一个被发现的细胞穿透肽,它凭借一种无毒的、高效的方式进入细胞。
跨膜机理
不同的细胞穿透肽(CPP)跨膜机制不同,一个细胞穿透肽(CPP)的具体机制有赖于几个参数,如分子大小(携带物质)、温度、细胞类型和细胞内外的稳定性等。细胞穿透肽(CPP)进入细胞的具体机制目前还不清楚,比较流行的推测包括以下三种:
A:倒置胶粒模型(invertedmicellemodel),CPPs通过细胞膜上磷脂分子的移动形成倒置胶粒结构,而进入胞浆。
B:直接穿透,即孔隙结构模型(poreformationmodel),CPPs在细胞膜上组成跨膜的孔隙结构而进入胞浆。
C:内吞方式进行细胞摄取。
来源:Cell-penetratingpeptidesandtheirtherapeuticapplications,VictoriaSebbage,BioscienceHorizons,Volume2,Number1,March2009.
CPPS序列
名称来源序列
Tatfamily
Tat(48-60)HIV-1proteinGRKKRRQRRRPPQQ
OligoarginineTatderivativeRn
Penetraliafamily
p-AntpAntermapediahomeodomainRQIKIWFQNRRMKWKK
plslIgl-1homeodomainRVIRVWFQNKRCKDKK
ChimericCPPs
TransportanGalanin-mastoparanGWTLNSAGYLLGKINLKALAALAKKIL
MPGpeptides
P-betagp41-SV40GALFLGFLGAAGSTMGAWSQPKKKRKV
P-alphagp41-SV40GALFLAFLAAALSLMGLWSQPKKKRRV
Pep-1Trp-richmotif-SV40KETWWETWWTEWSQPKKKRRV
细胞穿透肽HIVTAT
细胞穿透肽(如HIVTAT)可以以直接穿透和内吞两种方式进入细胞。HIVTAT或者简单的多聚精氨酸可被设计作为有效的药物载体,但CPP(如HIVTAT)是如何实现胞膜转运,目前仍不清楚。
简单的HIVTAT是如何促进象直接穿透和内吞作用的入胞机制的呢?来自GerardWong实验室的研究人员研究了在不同的条件下,HIVTAT是如何与细胞质膜、细胞骨架、特异的胞膜受体相互作用,从而诱导了多重转运途径。
有趣的是,TAT在不同条件下可与同一序列发生多种不同的反应,因而与胞膜、细胞骨架、特异受体相互作用可产生多种转运途径。
CPP的跨膜机制与多肽序列存在很敏感的关系,如果在一个纯亲水性的CPP中增加一个疏水残基,就能彻底地改变其转运机制,例如,最简单的CPP原型-多聚精氨基(polyR),可以诱导细胞膜上形成跨膜的孔隙结构。疏水氨基酸通过插入胞膜来形成正曲率,精氨酸可同时形成正曲率和负曲率,赖氨酸只能沿一个方向形成负曲率,这就意味着在精氨酸与赖氨酸/疏水物之间存在补偿关系。
如果疏水性有助于形成负高斯曲率(Gaussiancurvature),那为什么TAT肽中的疏水含量相对较低呢?其原因是CPPs都是利用尽可能少的疏水基去形成saddle-splaycurvature。序列上的差异很可能只会在膜上诱导短暂的类似孔隙的跨膜结构,从而形成对CPP来说更短的孔隙寿命。由于CPP的氨基酸组成不同,TAT肽在有或无受体情况下都可以介导细胞内吞作用。
参照药物为rDNA的肽类产品,如果高纯度合成后如何申报存在争议,最近刚出指南草案,给出了一些意见,见附件。
其中该指南指出五种肽,胰高血糖素、利拉鲁肽、奈西立肽、特立帕肽、替度鲁肽。这一类品种都是属于小于等于40aa的肽类产品,其余类似的品种应该也可以参考。
其中提出一些注意事项:
杂质分布相似--------这个还挺难的,不同途径出来的杂质不同,降解杂质会比较一致。化学合成肯定有新的种类,对合成与纯化工艺也是挑战;
对于每种相关的杂质证明合成中杂质水平相同或者更低;
证明合成肽不含超过药物成分0.5%的任何新杂质;
鉴定新的肽相关杂质;
对新的肽相关杂质论证不影响安全性和有效性----------------其中包括免疫原性是个大问题,具体如何做可能需要关注;
说到底就是要去除的非常干净就容易获批。
ANDAsforCertainHighlyPurifiedSyntheticPeptideDrugProductsThatRefertoListedDrugsofrDNAOrigin.pdf(104.95k)
比如,我需要Amitriptyline,阿密曲替林(一种抗抑郁药)。找哪家公司购买比较好?
另外,说明书上会有保存温度吗?
一般合成的都是粉末状的吧,溶解于溶剂后多少度保存比较好呢?
1.这是我找试剂商购买的进口药,但上面没有显示保存温度以及溶解后的保存温度。求各位大神给我一个建议
2.这是通过casnumber查到的相关信息
性质是易溶于水、甲醇、氯仿的。
但上面那个说明书又是显示轻微溶解于水、甲醇、氯仿的。
这下就有点矛盾了,不知道该相信谁了
比如硝苯地平的合成反应可以写成一步合成反应,除此之外还有哪些呢?来自刚入门的药物化学狗的提问,望各位大佬多多关照
很多战友在刚入的医药研发这个行业,对于药品的信息检索可能不是很了解,不知道怎么样才能正确高效的查询到自己想要的信息。我自己做了一个适合刚入门的研发人员看的资料和文献检索ppt,介绍了化合物合成,理化性质,专利和参比制剂等资料的检索。每一项内容都具体用药物做演示,看完你就能大体上明白怎么样利用这些资源去查找相关的信息,当然这个资料仅供那些刚毕业或刚如医药研发的战友参考。希望能帮助到那些刚入这行,也不知道怎么查询资料的战友!
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