2. Academic Validation
  3. 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

  • Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19512-7. doi: 10.1073/pnas.0709443104.
Mai Nguyen 1,  Richard C Marcellus,  Anne Roulston,  Mark Watson,  Lucile Serfass,  S R Murthy Madiraju,  Daniel Goulet,  Jean Viallet,  Laurent Bélec,  Xavier Billot,  Stephane Acoca,  Enrico Purisima,  Adrian Wiegmans,  Leonie Cluse,  Ricky W Johnstone,  Pierre Beauparlant,  Gordon C Shore
Affiliations

Affiliation

  • 1 Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, QC, Canada.
PMID: 18040043 DOI: 10.1073/pnas.0709443104
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.

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