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Rebastinib

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Chemical Structure| 1020172-07-9 同义名 : DCC-2036
CAS号 : 1020172-07-9
货号 : A104117
分子式 : C30H28FN7O3
纯度 : 99%+
分子量 : 553.587
MDL号 : MFCD19443646
存储条件：

粉末 Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(90.32 mM)，配合低频超声，并水浴加热至45℃助溶，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：

0.5% CMC+0.25% Tween 80+water 16 mg/mL suspension

生物活性
靶点

  • Abl

    p-Abl1 (native), IC50:0.75 nM

    u-Abl1 (T315I), IC50:5 nM
描述 Bcr-Abl is a constitutively active tyrosine kinase that drives survival and proliferation through multiple downstream pathways[3]. DCC-2036 is a Bcr-Abl inhibitor for Abl1WT, Abl1T315I and Abl1H396P with IC50 values of 0.8 nM, 4 nM and 1.4 nM, respectively[1]. In vitro, DCC-2036 effectively inhibited proliferation of the Ba/F3 cells expressing Bcr-Abl1WT with IC50 values of 5.4 nM, but DCC-2036 also retained potency against Ba/F3 cells expressing Bcr-Abl1 mutants that was resistant to imatinib, dasatinib, and nilotinib. DCC-2-35 also inhibited proliferation of the Ba/F3 cells expressing Bcr-Abl1T315I and the Ph+ cell line K562 with IC50 values of 13 nM and 5.5 nM, respectively. In addition, DCC-2036 inhibited proliferation of several common TKI-resistant mutants of Bcr- Abl1, including G250E, Q252H, Y235F, E255K, V299L, F317L, and M351T, at IC50 values ranging from 6 – 150 nM. DCC-2036 effectively inhibited autophosphorylation of Bcr-Abl1WT and Bcr-Abl1T315I with IC50 values of 29 nM and 18 nM, respectively, as well as the phosphorylation of STAT5 in Ba/F3 cells expressing Bcr-Abl1WT or Bcr-Abl1T315I with IC50 values of 28 nM and 13 nM, respectively. In vivo, a single oral dose of DCC-2036 at 100 mg/kg afforded circulating plasma levels that exceeded 12 μM for up to 24 hour, and effectively inhibited Bcr-Abl1 signaling for up to 8 hours in Ba/F3-Bcr-Abl1T315I leukemia cells isolated from bone marrow and spleen of tumor-bearing mice, as assessed by intracellular flow cytometric staining for phospho-STAT5. Oral administration of DCC-2036 at 100 mg/kg twice daily significantly prolonged the survival of the mice bearing Ba/F3- Bcr-Abl1T315I leukemia cells and reduced the leukemia cell burden in the spleens. Oral administration of DCC-2036 at doses of 60 - 100 mg/kg/d prolonged survival and reduced circulating leukemia cells in physiologically relevant mouse models of CML-like myeloproliferative neoplasia and Ph+ B-cell acute lymphoblastic leukemia induced by Bcr-Abl1T315I[1].
作用机制 DCC-2036 potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation[1].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.81mL

0.36mL

0.18mL

9.03mL

1.81mL

0.90mL

18.06mL

3.61mL

1.81mL
参考文献

[1]Chan W W, Wise S C, Kaufman M, 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.

[2]Eide CA, Adrian LT, et al. The ABL switch control inhibitor DCC-2036 is active against the chronic myeloid leukemia mutant BCR-ABLT315I and exhibits a narrow resistance profile. Cancer Res. 2011 May 1;71(9):3189-95.

[3]Ohare T, Deininger M W, Eide C A, et al. Targeting the BCR-ABL Signaling Pathway in Therapy-Resistant Philadelphia Chromosome-Positive Leukemia. Clinical Cancer Research, 2011, 17(2): 212-221.