Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Boronic Acids / pharmacology
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Bortezomib
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Cell Line, Tumor
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Cysteine Proteinase Inhibitors / pharmacology
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Drug Resistance, Neoplasm / drug effects*
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Humans
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Indoles
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Melanoma / metabolism
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Mice
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Mitochondria / drug effects
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Mitochondria / metabolism
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / metabolism
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Proteasome Inhibitors
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyrazines / pharmacology
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Pyrroles / pharmacology*
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bcl-2 Homologous Antagonist-Killer Protein / antagonists & inhibitors
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
Substances
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Antineoplastic Agents
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Boronic Acids
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Cysteine Proteinase Inhibitors
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Indoles
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Mcl1 protein, mouse
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Proteasome Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Pyrazines
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Pyrroles
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bcl-2 Homologous Antagonist-Killer Protein
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Bortezomib
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obatoclax