NDLI: Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis

Content Provider	PubMed Central
Author	Nguyen, Mai Marcellus, Richard C. Roulston, Anne Watson, Mark Serfass, Lucile Murthy, Madiraju S. R. Goulet, Daniel Viallet, Jean Laurent, Bélec Billot, Xavier Stephane, Acoca Purisima, Enrico Adrian, Wiegmans Cluse, Leonie Johnstone, Ricky W. Beauparlant, Pierre Shore, Gordon C.
Copyright Year	2007
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.
Related Links	http://dx.doi.org/10.1073/pnas.0709443104
Ending Page	19517
Page Count	6
Starting Page	19512
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	49
Volume Number	104
Language	English
Publisher	National Academy of Sciences
Publisher Date	2007-12-04
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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