The novel small molecular BH3 mimetics SM3 and its regulation of cell apoptosis and autophagy
The novel small molecular BH3 mimetics SM3 and its regulation of cell apoptosis and autophagy
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新型小分子BH3模拟物SM3及其对细胞凋亡和自噬的调控
DOI：
10.1016/j.bbrc.2019.06.068
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发表时间：
2019
影响因子：
3.1
通讯作者：
Xuejun Li
中科院分区：
文献类型：
--
作者：
Yefan Wang;Shengjun Fan;Xin Li;Yilixiati Xiaokaiti;Yan Pan;Lu Tie;Xuejun Li
BCL-2家族蛋白在细胞存活和死亡的调控中发挥着重要作用。抑制Bcl2家族的抗凋亡蛋白可导致肿瘤细胞的凋亡。BH3类药物是针对抗细胞凋亡蛋白Bcl2家族的小分子药物开发的。BH3模拟物已被证明对白血病细胞的凋亡和增殖有影响，其中一些已用于一期或二期临床试验。此外，随着自噬细胞死亡研究的深入，自噬和细胞凋亡的拮抗和协同作用在细胞死亡中具有重要意义。作为这两条细胞死亡途径的枢纽，Bcl2蛋白是基础研究和临床应用的潜在靶点。在我们的研究中，我们通过基于药效团的虚拟筛选，从14万个小分子化合物中发现了32个潜在的BH3模拟化合物。此外，我们还证实了32个潜在的BH3模拟物之一的Sm3在A549 细胞中同时诱导自噬和凋亡，并呈剂量-时间依赖关系。SM3通过内源性凋亡途径诱导细胞凋亡，并通过减弱Beclin-1和Bcl2复合体之间的相互作用诱导自噬。希望为今后新化合物的结构优化和进一步研究提供证据和线索。
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.