Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis
Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis
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DOI：
10.1073/pnas.0709443104
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发表时间：
2007-12-04
影响因子：
11.1
通讯作者：
Shore, Gordon C.
中科院分区：
文献类型：
--
作者：
Nguyen, Mai;Marcellus, Richard C.;Shore, Gordon C.
Bcl-2促生存蛋白家族成员的高表达可使癌细胞对凋亡产生抵抗。小分子obtoclax(GX15-070)被预测占据bcl2的BH3结合槽中的疏水口袋，它拮抗这些成员并诱导细胞凋亡，依赖于Bax和BAK。在酵母中的重组证实obtoclax作用于该途径，并克服了bcl2-、bclxl-、bclw-和mcl1介导的对bax或BAK的抗性。该化合物能有效地干扰完整线粒体外膜上MCL-1与BAK的直接相互作用，并抑制完整细胞内MCL-1与BAK的结合。研究表明，MCL-1对bcl2/bclxl/bclw-选择性拮抗剂ABT-737和蛋白酶体抑制剂bortezomib具有耐药性。在这两种情况下，这种抗性都被Obtoclax克服了。这些发现支持该化合物在癌症适应症或治疗中合理的临床开发机会，在这些癌症适应症或治疗中，MCL-1有助于抵抗细胞杀伤。
Elevated expression of members of the BCL-2 pro-survival family of proteins can confer resistance to apoptosis in cancer cells. Small molecule obatoclax (GX15-070), which is predicted to occupy a hydrophobic pocket within the BH3 binding groove of BCL-2, antagonizes these members and induces apoptosis, dependent on BAX and BAK. Reconstitution in yeast confirmed that obatoclax acts on the pathway and overcomes BCL-2-, BCL-XL-, BCL-w-, and MCL-1-mediated resistance to BAX or BAK. The compound potently interfered with the direct interaction between MCL-1 and BAK in intact mitochondrial outer membrane and inhibited the association between MCL-1 and BAK in intact cells. MCL-1 has been shown to confer resistance to the BCL-2/BCL-XL/BCL-w-selective antagonist ABT-737 and to the proteasome inhibitor bortezomib. In both cases, this resistance was overcome by obatoclax. These findings support a rational clinical development opportunity for the compound in cancer indications or treatments where MCL-1 contributes to resistance to cell killing.