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. doi: 10.1073/pnas.0709443104. Epub 2007 Nov 26.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Boronic Acids / pharmacology
  • Bortezomib
  • Cell Line, Tumor
  • Cysteine Proteinase Inhibitors / pharmacology
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Indoles
  • Melanoma / metabolism
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism
  • Proteasome Inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyrazines / pharmacology
  • Pyrroles / pharmacology*
  • bcl-2 Homologous Antagonist-Killer Protein / antagonists & inhibitors
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • Cysteine Proteinase Inhibitors
  • Indoles
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proteasome Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrazines
  • Pyrroles
  • bcl-2 Homologous Antagonist-Killer Protein
  • Bortezomib
  • obatoclax