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Ponatinib (AP24534)

现货
Catalog No.
A5467
pan-BCR-ABL抑制剂,多激酶抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 550.00
现货
5mg
¥ 500.00
现货
25mg
¥ 1,440.00
现货
100mg
¥ 3,040.00
Ship with 10-15 days

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Background

BCR-ABL fusion gene forms when the ABL gene from chromosome 9 joins to the BCR gene on chromosome 22. BCR-ABL is translated into a constitutively active tyrosine kinase, which is oncogenic. Depending on the fusion location, multiple protein variants are formed with molecular weight ranging from 185 to 210 kDa. BCR-ABL activates JAK/STAT pathway and MAPK signaling. [3] This gene is found in most patients with chronic myelogenous leukemia (CML), and in some patients with acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML).

Ponatinib is the second-generation pan inhibitor of BCR-Abl kinases, which is also effective against the mutant form of BCR-Abl (T315I). [1, 2] IC50 for WT and mutant form are 0.5 and 11 nM. [4] Ponatinib also inhibits several other clinically relevant kinases (RET, FLT3, KIT, PDGFRα, PDGFRβ, and FGFR1) in vitro, with IC50s of 5, 25, 100, 5, 9, and 23) in Ba/F3 cells lines. [4]

References:
1. Huang WS, Metcalf CA, Sundaramoorthi R, Wang Y, Zou D, Thomas RM, Zhu X, Cai L, Wen D, Liu S, Romero J, Qi J, Chen I, Banda G, Lentini SP, Das S, Xu Q, Keats J, Wang F, Wardwell S, Ning Y, Snodgrass JT, Broudy MI, Russian K, Zhou T, Commodore L, Narasimhan NI, Mohemmad QK, Iuliucci J, Rivera VM, Dalgarno DC, Sawyer TK, Clackson T, Shakespeare WC (June 2010). Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl) methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J. Med. Chem. 53 (12): 4701–19.
2. O'Hare T, Pollock R, Stoffregen EP, Keats JA, Abdullah OM, Moseson EM, Rivera VM, Tang H, Metcalf Ca CA, Bohacek RS, Wang Y, Sundaramoorthi R, Shakespeare WC, Dalgarno D, Clackson T, Sawyer TK, Deininger MW, Druker BJ (2004). Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML. Blood 104 (8): 2532–2539.
3. Cilloni D and Saglio G. Molecular pathways: BCR-ABL. Clinical Cancer Res (2011) 18(4):930-937
4. Gozgit JM, Wong MJ, Zhu X, Schrock AB, Chen T, Clackson T and Rivera VM. Ponatinib, a potent pan-BCR-ABL inhibitor, retains activity against gatekeeper mutants of FLT3, RET, KIT, PDGFR α/β and FGFR1. 2012 AACR poster.

文献引用

Physical AppearanceA solid
StorageStore at -20°C
M.Wt532.56
Cas No.943319-70-8
FormulaC29H27F3N6O
Solubility≥53.3mg/mL in DMSO, <2.45 mg/mL in EtOH, <2.31 mg/mL in H2O
Chemical Name3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide
SDFDownload SDF
Canonical SMILESCC1=C(C=C(C=C1)C(=O)NC2=CC(=C(C=C2)CN3CCN(CC3)C)C(F)(F)F)C#CC4=CN=C5N4N=CC=C5
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。
细胞实验: [1]

细胞系

稳定表达ZMYM2-FGFR1和CEP110-FGFR1或BCR-FGFR1的BaF3细胞

制备方法

该化合物在DMSO中的溶解度大于10 mM,若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

48 hours,50 nM for BaF3-ZMYM2,BAF3-CEP;100 nM for BaF3-BCR

实验结果

Ponatinib治疗降低磷酸化FGFR1水平。在三种不同的嵌合激酶转化的BaF3细胞中,S期细胞的百分比急剧下降,而凋亡细胞的百分比增加,这表明它们的存活依赖于活化的FGFR1。

动物实验: [2]

动物模型

注射MV4-11细胞的雌性CB.17严重联合免疫缺陷小鼠

给药剂量

口服给药,1-25 mg/kg,每日一次,持续4周

实验结果

Ponatinib以剂量依赖性方式有效抑制肿瘤生长。测试的最低剂量1 mg/kg的Ponatinib显著抑制肿瘤生长,TGI 为46%(P <0.01),2.5 mg/kg或更大的剂量导致肿瘤消退。值得注意的是,给予10或25 mg/kg的Ponatinib导致完全和持久的肿瘤消退,在31天的随访期间没有检测到可触摸到的肿瘤。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1] Ren M, Qin H, Ren R, Cowell JK. Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities. Leukemia. 2013 Jan;27(1):32-40.

[2] Gozgit JM, Wong MJ, Wardwell S, Tyner JW, Loriaux MM, Mohemmad QK, Narasimhan NI, Shakespeare WC, Wang F, Druker BJ, Clackson T, Rivera VM. Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Mol Cancer Ther. 2011 Jun;10(6):1028-35.

描述 Ponatinib(AP24534)是一种新型的多靶点抑制剂,可抑制Abl、PDGFRα、VEGFR、FGFR1和Src蛋白,IC50值分别为0.37 nM、1.1 nM、1.5 nM、2.2 nM和5.4 nM。
靶点 Abl PDGFRα VEGFR2 FGFR1 Src  
IC50 0.37 nM 1.1 nM 1.5 nM 2.2 nM 5.4 nM  

化学结构

Ponatinib (AP24534)

相关生物数据

Ponatinib (AP24534)

相关生物数据

Ponatinib (AP24534)

相关生物数据

Ponatinib (AP24534)

相关生物数据

Ponatinib (AP24534)