A Small-Molecule Inhibitor of Bax and Bak Oligomerization Prevents Genotoxic Cell Death and Promotes Neuroprotection PMID: 28392146

ADC Targets in Oncology

2026-04-10

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

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].

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.