An Inhibitor of the Interaction of Survivin with Smac in Mitochondria Promotes Apoptosis

Seong Hyun Park, Insu Shin, Sang Hyun Park, Nam Doo Kim, Injae Shin

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Abstract

Herein we report the first small molecule that disrupts the survivin-Smac interaction taking place in mitochondria. The inhibitor, PZ-6-QN, was identified by initially screening a phenothiazine library using a fluorescence anisotropy assay and then conducting a structure–activity relationship study. Mutagenesis and molecular docking studies suggest that PZ-6-QN binds to survivin similarly to the known Smac peptide, AVPI. The results of the effort also show that PZ-6-QN exhibits good anticancer activity against various cancer cells. Moreover, cell-based mechanistic studies provide evidence for the proposal that PZ-6-QN enters mitochondria to inhibit the survivin-Smac interaction and promotes release of Smac and cytochrome c from mitochondria into the cytosol, a process that induces apoptosis in cancer cells. Overall, the present study suggests that PZ-6-QN can serve as a novel chemical probe for study of processes associated with the mitochondrial survivin-Smac interaction and it will aid the discovery of novel anticancer agents.

Original languageEnglish
Pages (from-to)4035-4041
Number of pages7
JournalChemistry - An Asian Journal
Volume14
Issue number22
DOIs
Publication statusPublished - 2019 Nov 18

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Organic Chemistry

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