生物活性

• 靶点

  Bcl-2 IC50:3μMol/L

  Bfl-1 IC50:5μMol/L

  Mcl-1 IC50:2.9μMol/L

• 描述The B-cell lymphoma 2 (Bcl-2) family of proteins is composed of both antiapoptotic members, such as Bcl-2, Bcl-xL as well as Bcl-w, and proapoptotic members. Up-regulation of the pro-survival Bcl-2 family proteins is one of the primary means for cancer cells to evade apoptosis. Obatoclax is the BCL-2 family inhibitor with Ki value ranging in 1-7μM (measured by FP assays) for all the six members, BCL-2, BCL-XL, MCL-1, BCL-w, A1 and BCL-b of their cytosolic domains. The in vitro study showed that obatoclax at concentration of 10-500nM can potently inhibit the association of MCL-1 and BAK extracted from SK-Mel5 cells or in intact mitochondria. Obatoclax can induce apoptosis and inhibit colony formation in cells dependent of BAX or BAK. Treatment with 0.1μM obatoclax overcame MCL-1-mediated resistance to ABT-737, leading to cell death in combination, as well as caused a modest increase of BID, NOXA, BIM and PUMA, the BH3-only members reported to antagonize MCL-1 in KB/BCL-2 cells over-expressing BCL-2. Also obatoclax can overcome MCL-1-mediated resistance to bortezomib. Treatment with obatoclax at concentration of 50 or 500nM for 24h significantly increased the apoptosis in mouse melanoma B16-F1 cells. These suggested that obatoclax may be the potential compound used to treatment where MCL-1 contributes to resistance to cell killing^[1]. Obatoclax at dose of 3mg/kg markedly potentiated carfilzomib-induced-tumor growth suppression in an in vivo SUDHL4 xenograft model^[2].
• 作用机制Obatoclax can occupy a hydrophobic pocket within the BH3 binding groove of BCL-2 and thus interferes with MCL-1/BAK interactions.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  22RV1	-	Growth Inhibition Assay	-	IC50=0.27378 μM	SANGER
  23132-87	-	Growth Inhibition Assay	-	IC50=0.82843 μM	SANGER
  5637	-	Growth Inhibition Assay	-	IC50=0.08367 μM	SANGER

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• 动物研究
  剂量	Nude Mice: 1.25 mg/kg - 5 mg/kg[3] (i.v.)
  给药途径	i.v.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01150656	-	-	Completed	-	-
  NCT00438178	Hematological Malignancies	Phase 1	Completed	-	United States, District of Col... more >>umbia Georgetown University Medical Center Washington, District of Columbia, United States, 20007 United States, Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Canada, Ontario Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 Collapse <<
  NCT00360035	Myelofibrosis	Phase 2	Completed	-	United States, District of Col... more >>umbia Georgetown University Medical Center Washington, District of Columbia, United States, 20007 United States, Florida James A. Haley Veterans Hospital Tampa, Florida, United States, 33612 United States, Georgia Emory University Atlanta, Georgia, United States, 30322 United States, Illinois The University of Chicago Chicago, Illinois, United States, 60637 United States, Massachusetts University of Massachusetts Medical Center Worcester, Massachusetts, United States, 01655 United States, Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Canada, Ontario Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 Collapse <<

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• 参考文献

• [1] Nguyen M, Marcellus RC, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19512-7. Epub 2007 Nov 26.

  [2] Dasmahapatra G, Lembersky D, et al. Obatoclax interacts synergistically with the irreversible proteasome inhibitor carfilzomib in GC- and ABC-DLBCL cells in vitro and in vivo. Mol Cancer Ther. 2012 May;11(5):1122-32.