<br>基于 E3 结合剂研究发现一种高效、选择性的 BRD9 PROTAC 降解剂，用于治疗血液肿瘤,Journal of Medicinal Chemistry

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基于 E3 结合剂研究发现一种高效、选择性的 BRD9 PROTAC 降解剂，用于治疗血液肿瘤
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-06-24 , DOI: 10.1021/acs.jmedchem.4c00883
Haiting Duan ₁ , Jingyu Zhang _{1,

2,

3} , Renzhao Gui _{4,

5} , Yang Lu ₁ , Ao Pang ₁ , Beijing Chen ₄ , Liteng Shen ₁ , Hengyuan Yu ₆ , Jia Li _{4,

5,

7,

8} , Tengfei Xu ₆ , Yuwei Wang ₉ , Xiaojun Yao ₁₀ , Bo Zhang _{2,

3} , Nengming Lin _{2,

3} , Xiaowu Dong _{1,

6} , Yubo Zhou _{4,

5,

7} , Jinxin Che _{1,

6}

Affiliation

Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Cancer Center of Zhejiang University, Hangzhou 310006, P. R. China.
Department of Clinical Pharmacology, Hangzhou Geriatric Hospital, Hangzhou, Zhejiang 310022, P. R. China.
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Tsuihang New District, Zhongshan, Guangdong 528400, P. R. China.
School of Pharmacy, Zunyi Medical University, Zunyi 563000, P. R. China.
State Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, P. R. China.
College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712000, P. R. China.
Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, P. R. China.

BRD9 是参与癌症和炎症性疾病的关键表观遗传因子。尽管如此，靶向药物有限的选择性和较差的表型活性使其成为非典型的不可成药的靶点。 PROTAC 提供了解决该问题的替代策略。在这项研究中，我们探索了多种 E3 连接酶配体对 BRD9 PROTAC 降解的贡献。通过分子对接、结合亲和力分析和结构-活性关系研究，我们鉴定了一种高效的 PROTAC E5 ，具有出色的 BRD9 降解 (DC ₅₀ = 16 pM) 和对 MV4-11 细胞的抗增殖作用 (IC ₅₀ = 0.27 nM) 和 OCI -LY10 细胞（IC ₅₀ = 1.04 nM）。 E5可以选择性降解BRD9并诱导细胞周期停滞和凋亡。此外， E5的治疗功效在异种移植肿瘤模型中得到了证实，并伴随着进一步的RNA-seq分析。因此，这些结果可能为高效PROTAC降解剂的发现和研究铺平道路并提供参考。

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更新日期：2024-06-24

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