Discovery and identification of a novel small molecule BCL-2 inhibitor that binds to the BH4 domain

Jing-yi Zhou1, Rui-rui Yang2,3,4, Jie Chang1,2, Jia Song2,5, Zi-sheng Fan1,2, Ying-hui Zhang2,3, Cheng-hao Lu1,2, Hua-liang Jiang1,2,3, Ming-yue Zheng1,2,3, Su-lin Zhang2,3
1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China
2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
3 University of Chinese Academy of Sciences, No. 19 A Yuquan Road, Beijing 100049, China
4 Shanghai Institute for Advanced Immunochemical Studies, and School of Life Science and Technology, ShanghaiTech University, 393 Huaxiazhong Road, Shanghai 200031, China
5 The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
Correspondence to: Hua-liang Jiang:, Ming-yue Zheng:, Su-lin Zhang:,
DOI: 10.1038/s41401-022-00936-0
Received: 6 February 2022
Accepted: 2 June 2022
Advance online: 2 August 2022


The B-cell lymphoma 2 (BCL-2) protein family plays a pivotal role in regulating the apoptosis process. BCL-2, as an antiapoptotic protein in this family, mediates apoptosis resistance and is an ideal target for cell death strategies in cancer therapy. Traditional treatment modalities target BCL-2 by occupying the hydrophobic pocket formed by BCL-2 homology (BH) domains 1–3, while in recent years, the BH4 domain of BCL-2 has also been considered an attractive novel target. Herein, we describe the discovery and identification of DC-B01, a novel BCL-2 inhibitor targeting the BH4 domain, through virtual screening combined with biophysical and biochemical methods. Our results from surface plasmon resonance and cellular thermal shift assay confirmed that the BH4 domain is responsible for the interaction between BCL-2 and DC-B01. As evidenced by further cell-based experiments, DC-B01 induced cell killing in a BCL-2-dependent manner and triggered apoptosis via the mitochondria-mediated pathway. DC-B01 disrupted the BCL-2/c-Myc interaction and consequently suppressed the transcriptional activity of c-Myc. Moreover, DC-B01 inhibited tumor growth in vivo in a BCL‐2‐dependent manner. Collectively, these results indicate that DC-B01 is a promising BCL-2 BH4 domain inhibitor with the potential for further development.
Keywords: Bcl-2; BH4 domain; apoptosis; antitumor; virtual screening

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