title: A Small-Molecule Inhibitor of Bax and Bak Oligomerization Prevents Genotoxic Cell Death and Promotes Neuroprotection.
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.
authors.affiliation: 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.
authors.forename: Xin
authors.initials: X
authors.lastname: Niu
authors.affiliation: 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.
authors.forename: Hetal
authors.initials: H
authors.lastname: Brahmbhatt
authors.affiliation: 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.
authors.forename: Philipp
authors.initials: P
authors.lastname: Mergenthaler
authors.affiliation: Department of Biochemistry and Molecular Biology, Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Sang
authors.affiliation: Department of Medicinal Chemistry, Center for Tumor Biology and Immunology, Philipps Universität Marburg, 35043 Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Daude
authors.affiliation: Department of Medicinal Chemistry, Center for Tumor Biology and Immunology, Philipps Universität Marburg, 35043 Marburg, Germany.
authors.forename: Fabian G R
authors.initials: FGR
authors.lastname: Ehlert
authors.affiliation: Department of Medicinal Chemistry, Center for Tumor Biology and Immunology, Philipps Universität Marburg, 35043 Marburg, Germany.
authors.forename: Wibke E
authors.initials: WE
authors.lastname: Diederich
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
authors.forename: Eve
authors.initials: E
authors.lastname: Wong
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada.
authors.forename: Justin
authors.initials: J
authors.lastname: Pogmore
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON M5G 0A3, Canada.
authors.forename: Jyoti P
authors.initials: JP
authors.lastname: Nandy
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON M5G 0A3, Canada.
authors.forename: Maragani
authors.initials: M
authors.lastname: Satyanarayana
authors.affiliation: Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Jimmidi
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON M5G 0A3, Canada.
authors.forename: Prabhat
authors.initials: P
authors.lastname: Arya
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada; Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Leber
authors.affiliation: Department of Biochemistry and Molecular Biology, Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA.
authors.forename: Jialing
authors.initials: J
authors.lastname: Lin
authors.affiliation: Fachbereich Pharmazie, Institut für Pharmakologie und Klinische Pharmazie, Philipps Universität Marburg, 35043 Marburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Culmsee
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yi
authors.affiliation: 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.
authors.forename: David W
authors.initials: DW
authors.lastname: Andrews
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D002478:Cells, Cultured; D005260:Female; D018698:Glutamic Acid / Q000633:toxicity; D045325:HCT116 Cells; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D008297:Male; D051379:Mice; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D008081:Liposomes; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D018698:Glutamic Acid
keywords: Bak; Bax; Bcl-2 family; apoptosis; excitotoxicity; mitochondrial outer membrane permeabilization; programmed cell death; small-molecule inhibitors