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The novel small molecular BH3 mimetics SM3 and its regulation of cell apoptosis and autophagy

Author:
Wang, Yefan, Fan, Shengjun, Li, Xin, Xiaokaiti, Yilixiati, Pan, Yan, Tie, Lu, Li, Xuejun
Source:
Biochemical and biophysical research communications 2019 v.517 no.1 pp. 15-22
ISSN:
0006-291X
Subject:
antagonism, apoptosis, autophagy, cell viability, clinical trials, death, drugs, leukemia, pro-apoptotic proteins, proteins, screening, synergism
Abstract:
Bcl-2 family proteins play an important role in regulation of the cell survival and death. The inhibition of the anti-apoptotic proteins of Bcl-2 family leads to the apoptosis of cancer. BH3 mimetics have been developed targeting anti-apoptotic proteins of Bcl-2 family as small molecular drugs. It has been proved that BH3 mimetics has effect on apoptosis and proliferation in leukemia and some of them has been used in phase one or two clinical trials. Besides, with the development of the research on autophagic cell death, the antagonism and the synergism of autophagy and apoptosis is significant in cell death. As a hub of these two pathways of cell death, Bcl-2 protein is a potential target in basic research and clinical applications.In our studies, we found 32 potential BH3 mimetics compounds from 140,000 small molecular compounds via pharmacophore-based virtual screening. Furthermore, we demonstrated SM3, one of the 32 potential BH3 mimetics, induced autophagy and apoptosis simultaneously in dose-time dependence in A549 cell. SM3 induced apoptosis by intrinsic apoptosis pathway and induced autophagy by weakening the interaction between Beclin-1 and Bcl-2 complex. We wish to provide evidences and clues for the structural optimizing and further study of new compounds in the future.
Agid:
6473778