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http://dx.doi.org/10.5012/bkcs.2014.35.2.419

Identification of Inhibitors Against BAK Pore Formation using an Improved in vitro Assay System  

Song, Seong-Soo (Department of Chemistry, Kookmin University)
Lee, Won-Kyu (Department of Chemistry, Kookmin University)
Aluvila, Sreevidya (Department of Biochemistry & Molecular Biology, Rosalind Franklin University of Medicine and Science)
Oh, Kyoung Joon (Department of Biochemistry & Molecular Biology, Rosalind Franklin University of Medicine and Science)
Yu, Yeon Gyu (Department of Chemistry, Kookmin University)
Publication Information
Bulletin of the Korean Chemical Society / v.35, no.2, 2014 , pp. 419-424 More about this Journal
Abstract
The pro-apoptotic BCL-2 family protein BID activates BAK and/or BAX, which form oligomeric pores in the mitochondrial outer membrane. This results in the release of cytochrome c into the cytoplasm, initiating the apoptotic cascade. Here, we utilized liposomes encapsulating sulfo-rhodamine at a controlled temperature to improve upon a previously reported assay system with enhanced sensitivity and specificity for measuring membrane permeabilization by BID-dependent BAK activation. BAK activation was inhibited by BCL-$X_L$ protein but not by a mutant protein with impaired anti-apoptotic activity. With the assay system, we screened a chemical library and identified several compounds including trifluoperazine, a mitochondrial apoptosis-induced channel blocker. It inhibited BAK activation by direct binding to BAK and blocking the oligomerization of BAK.
Keywords
BAK; BAX; Trifluoperazine; Apoptosis; High throughput;
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