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

Xin Niu; Hetal Brahmbhatt; Philipp Mergenthaler; Zhi Zhang; Jing Sang; Michael Daude; Fabian G R Ehlert; Wibke E Diederich; Eve Wong; Weijia Zhu; Justin Pogmore; Jyoti P Nandy; Maragani Satyanarayana; Ravi K Jimmidi; Prabhat Arya; Brian Leber; Jialing Lin; Carsten Culmsee; Jing Yi; David W Andrews

doi:10.1016/j.chembiol.2017.03.011

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. Epub 2017 Apr 6.

Authors

Xin Niu¹, Hetal Brahmbhatt², Philipp Mergenthaler³, Zhi Zhang⁴, Jing Sang⁵, Michael Daude⁶, Fabian G R Ehlert⁶, Wibke E Diederich⁶, Eve Wong⁷, Weijia Zhu⁷, Justin Pogmore⁸, Jyoti P Nandy⁹, Maragani Satyanarayana⁹, Ravi K Jimmidi¹⁰, Prabhat Arya⁹, Brian Leber¹¹, Jialing Lin⁴, Carsten Culmsee¹², Jing Yi¹³, David W Andrews¹⁴

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: david.andrews@sri.utoronto.ca.

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.

MeSH terms

Animals
Apoptosis / drug effects*
Binding Sites
Cells, Cultured
Female
Glutamic Acid / toxicity
HCT116 Cells
Humans
Liposomes / metabolism
Male
Mice
Mitochondrial Membranes / drug effects*
Mitochondrial Membranes / metabolism
Neurons / cytology
Neurons / drug effects
Neurons / metabolism
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Permeability / drug effects
Protein Multimerization / drug effects
Protein Structure, Tertiary
Recombinant Proteins / biosynthesis
Recombinant Proteins / chemistry
Recombinant Proteins / isolation & purification
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship
bcl-2 Homologous Antagonist-Killer Protein / antagonists & inhibitors
bcl-2 Homologous Antagonist-Killer Protein / genetics
bcl-2 Homologous Antagonist-Killer Protein / metabolism*
bcl-2-Associated X Protein / antagonists & inhibitors
bcl-2-Associated X Protein / genetics
bcl-2-Associated X Protein / metabolism*

Substances

Liposomes
Neuroprotective Agents
Recombinant Proteins
Small Molecule Libraries
bcl-2 Homologous Antagonist-Killer Protein
bcl-2-Associated X Protein
Glutamic Acid

Grants and funding

R01 GM062964/GM/NIGMS NIH HHS/United States