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  3. A Small-Molecule Inhibitor of Bax and Bak Oligomerization Prevents Genotoxic Cell Death and Promotes Neuroprotection

A Small-Molecule Inhibitor of Bax and Bak Oligomerization Prevents Genotoxic Cell Death and Promotes Neuroprotection

  • Cell Chem Biol. 2017 Apr 20;24(4):493-506.e5. doi: 10.1016/j.chembiol.2017.03.011.
Xin Niu 1,  Hetal Brahmbhatt 2,  Philipp Mergenthaler 3,  Zhi Zhang 4,  Jing Sang 5,  Michael Daude 6,  Fabian G R Ehlert 6,  Wibke E Diederich 6,  Eve Wong 7,  Weijia Zhu 7,  Justin Pogmore 8,  Jyoti P Nandy 9,  Maragani Satyanarayana 9,  Ravi K Jimmidi 10,  Prabhat Arya 9,  Brian Leber 11,  Jialing Lin 4,  Carsten Culmsee 12,  Jing Yi 13,  David W Andrews 14
Affiliations

Affiliations

  • 1 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada; Department of Biochemistry and Molecular Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 2 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada; Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada.
  • 3 Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada; Departments of Experimental Neurology and Neurology, Center for Stroke Research, NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Berlin Institute of Health, 10117 Berlin, Germany.
  • 4 Department of Biochemistry and Molecular Biology, Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA.
  • 5 Department of Biochemistry and Molecular Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada.
  • 6 Department of Medicinal Chemistry, Center for Tumor Biology and Immunology, Philipps Universität Marburg, 35043 Marburg, Germany.
  • 7 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • 8 Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada.
  • 9 Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON M5G 0A3, Canada.
  • 10 Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
  • 11 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada; Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • 12 Fachbereich Pharmazie, Institut für Pharmakologie und Klinische Pharmazie, Philipps Universität Marburg, 35043 Marburg, Germany.
  • 13 Department of Biochemistry and Molecular Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 14 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada; Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada. Electronic address: [email protected].
PMID: 28392146 DOI: 10.1016/j.chembiol.2017.03.011
Abstract

Aberrant Apoptosis can lead to acute or chronic degenerative diseases. Mitochondrial outer membrane permeabilization (MOMP) triggered by the oligomerization of the Bcl-2 Family proteins Bax/Bak is an irreversible step leading to execution of Apoptosis. Here, we describe the discovery of small-molecule inhibitors of Bax/Bak oligomerization that prevent MOMP. We demonstrate that these molecules disrupt multiple, but not all, interactions between Bax dimer interfaces thereby interfering with the formation of higher-order oligomers in the MOM, but not recruitment of Bax to the MOM. Small-molecule inhibition of Bax/Bak oligomerization allowed cells to evade apoptotic stimuli and rescued neurons from death after excitotoxicity, demonstrating that oligomerization of Bax is essential for MOMP. Our discovery of small-molecule Bax/Bak inhibitors provides novel tools for the investigation of the mechanisms leading to MOMP and will ultimately facilitate development of compounds inhibiting Bax/Bak in acute and chronic degenerative diseases.

Keywords

Bak; Bax; Bcl-2 family; apoptosis; excitotoxicity; mitochondrial outer membrane permeabilization; programmed cell death; small-molecule inhibitors.

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