Rebastinib (DCC-2036) 是一种口服有效的

Rebastinib  (Synonyms: DCC-2036)

Rebastinib (DCC-2036) 是一种口服有效的，非 ATP 竞争性的 Bcr-Abl 抑制剂，作用于 Abl1^WT 和 Abl1^T315I，IC₅₀ 分别为 0.8 nM 和 4 nM，也抑制 SRC，KDR，FLT3 和 Tie-2，低活性作用于c-Kit。

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生物活性    
Rebastinib (DCC-2036) is an orally active, non-ATP-competitive Bcr-Abl inhibitor for Abl1WT and Abl1T315I with IC50s of 0.8 nM and 4 nM, respectively. Rebastinib also inhibits SRC, KDR, FLT3, and Tie-2, and has low activity to seen towards c-Kit.

IC50 & Target    
IC50: 0.75±0.11 nM (ABL1WT), 2±0.3 nM (FLT3), 4±0.3 nM (KDR), 6±0.3 nM (TIE2), 34±6 nM (SRC)[1]

体外研究(In Vitro)    
Rebastinib potently (IC50 0.82 nM) inhibits u-ABL1native, which is thought to exist predominantly in the inactive type II conformation. In addition, Rebastinib also strongly inhibits p-ABL1native (IC50 2 nM), which more readily adopts an active, Type I conformation[1]. 
Rebastinib potently inhibits both u-ABL1T315I (IC50 5 nM) and p-ABL1T315I (IC50 4 nM), both of which exist predominately in the Type I conformation due to stabilization of an activating hydrophobic spine by the T315I mutation[1]. 
In addition to ABL1, Rebastinib also inhibits the SRC family kinases LYN, SRC, FGR, and HCK, and PDGFRα, and PDGFRβ with IC50 of 29±1, 34±6, 38±1, 40±1, 70±10 and 113±10 nM, respectively. Notably, Rebastinib spared c-KIT (IC50 481 nM)[1]. 
Rebastinib effectively inhibits the proliferation of Ba/F3 cells expressing native BCR-ABL1native (IC50 5.4 nM). Rebastinib also inhibits proliferation of the Ph+ cell line K562 (IC50 5.5 nM)[1]. 
Rebastinib also inhibits proliferation of several common TKI-resistant mutants of BCR-ABL1, including G250E, Q252H, Y235F, E255K, V299L, F317L, and M351T, at IC50s ranging from 6-150 nM. Rebastinib effectively inhibits autophosphorylation of BCR-ABL1native (IC50 29 nM) and BCR-ABL1T315I (IC50 18 nM), as well as the phosphorylation of STAT5 in both cell lines (IC50 28 nM and 13 nM, respectively)[1]. 

体内研究(In Vivo)    
A single dose of Rebastinib (DCC-2036; oral; 100 mg/kg) affords circulating plasma levels that exceeds 12 μM for up to 24 hours, and effectively inhibits BCR-ABL1 signaling for up to 8 hours in Ba/F3-BCR-ABL1T315I leukemia cells isolated from BM and spleen of tumor-bearing mice[1]. 
Treatment of mice bearing Ba/F3-BCR-ABL1T315I leukemia cells with Rebastinib at 100 mg/kg once daily by oral gavage significantly prolonged their survival, while STI571 at 100 mg/kg twice daily is ineffective[1]. 
In this aggressive allograft model, Rebastinib is as effective for treatment of BCR-ABLT315I leukemia as STI571 at 100 mg/kg twice daily in BCR-ABL1native leukemia, and reduces the leukemia cell burden in the spleens of treated mice[1]. 

分子量    
553.59

性状    
Solid

Formula    
C30H28FN7O3

CAS 号    
1020172-07-9

运输条件    
Room temperature in continental US; may vary elsewhere.

储存方式    
Powder    -20°C    3 years
4°C    2 years
In solvent    -80°C    2 years
-20°C    1 year
溶解性数据    
In Vitro: 
DMSO : 50 mg/mL (90.32 mM; ultrasonic and warming and heat to 80°C)

配制储备液    
浓度溶剂体积质量    1 mg    5 mg    10 mg
1 mM    1.8064 mL    9.0320 mL    18.0639 mL
5 mM    0.3613 mL    1.8064 mL    3.6128 mL
10 mM    0.1806 mL    0.9032 mL    1.8064 mL
*
请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80℃, 2 years; -20℃, 1 year。-80℃ 储存时，请在 2 年内使用， -20℃ 储存时，请在 1 年 内使用。

In Vivo:
请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：

——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

1.
请依序添加每种溶剂： 10% DMSO    40% PEG300    5% Tween-80    45% saline

Solubility: ≥ 2.08 mg/mL (3.76 mM); Clear solution

2.
请依序添加每种溶剂： 10% DMSO    90% (20% SBE-β-CD in saline)

Solubility: ≥ 2.08 mg/mL (3.76 mM); Clear solution
 

参考文献	[1]. Chan WW, et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell. 2011, 19(4), 556-568.  [Content Brief]