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]

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