alexa Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis.
Oncology

Oncology

Journal of Leukemia

Author(s): Nguyen M, Richard C Marcellus, Anne Roulston, Mark Watson, Lucile Serfass, S R Murthy Madiraju, Daniel Goulet, Jean Viallet, Laurent Blec, Xavier Billot, Stephane Acoca, Enrico Purisima, Adrian Wiegmans, Leonie Cluse, Pierre Beauparlant, Gordon C Shore

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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.

This article was published in Proc Natl Acad Sci U S A and referenced in Journal of Leukemia

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