| Literature DB >> 18040043 |
Mai Nguyen1, 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.
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.Entities:
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Year: 2007 PMID： 18040043 PMCID： PMC2148320 DOI： 10.1073/pnas.0709443104
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205