Identification of inhibitors of Bcl-2 family protein-protein interaction by combining the BRET screening platform with virtual screening

被引：7
|
作者：
Park, I-Seul [1 ]
Seo, Haeng Ran [2 ]
Kim, Kideok [1 ]
Lee, Honggun [1 ]
Shum, David [1 ]
Choi, Inhee [3 ]
Kim, Jiho [1 ]
机构：
[1] Inst Pasteur Korea, Screening Discovery Platform, 16,Daewangpangyo Ro 712 Beon Gil, Seongnam Si 13488, Gyeonggi Do, South Korea
[2] Inst Pasteur Korea, Canc Biol Lab, 16,Daewangpangyo Ro 712 Beon Gil, Seongnam Si 13488, Gyeonggi Do, South Korea
[3] Inst Pasteur Korea, Med Chem, 16,Daewangpangyo Ro 712 Beon Gil, Seongnam Si 13488, Gyeonggi Do, South Korea
来源：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2020年 / 527卷 / 03期
基金：
新加坡国家研究基金会;
关键词：
Protein-protein interaction (PPI); Bioluminescence resonance energy transfer (BRET); Bcl-2; proteins; Virtual screening; Small-molecule modulators; BCL-X(L);
D O I：
10.1016/j.bbrc.2020.05.045
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Bcl-2 family proteins play key roles in tumor initiation, progression, and resistance to therapy. Therefore, the protein-protein interactions (PPIs) between the pro-survival proteins, B-cell lymphoma (Bcl)-2 and Bcl-xL, and the pro-apoptotic proteins, Bax and Bak, could be attractive therapeutic targets for anticancer drug discovery. Here, we found new small molecules, BIP-A1001 and BIP-A2001 that modulated Bak/Bax and Bcl-xL interactions by combining the Nanoluc/YFP-based bioluminescence resonance energy transfer (BRET) assay with structure based virtual screening. In addition, we chose compounds with similar structures to BIP-A1001 and BIP-A2001 and tested their inhibitory effects using the BRET assay as a dose-response function. The results indicated that identifying compounds that inhibit interactions between Bak/Bax and Bcl-xL could be a promising approach to enhance cancer therapy. (C) 2020 Elsevier Inc. All rights reserved.
引用
收藏
页码：709 / 715
页数：7
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