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

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

来源：Cell Chemical Biology, 2017, 24(4): 493-+.

DOI：10.1016/j.chembiol.2017.03.011

• CYTOCHROME-C RELEASE
• BCL-2 FAMILY
• MEMBRANE PERMEABILIZATION
• NEURONAL APOPTOSIS
• BH3-ONLY PROTEINS
• OUTER-MEMBRANE
• BH3 DOMAIN
• N-BAK
• MITOCHONDRIA
• ACTIVATION

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.

• 出版日期2017-4-20
• 单位上海交通大学; 河北医科大学