MALT1 Inhibitors and Degraders: Strategies for NF-κB-Driven Malignancies

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL Journal of Medicinal Chemistry Pub Date : 2025-02-25 DOI:10.1021/acs.jmedchem.4c02873
Ru-Yue Zhang, Zi-Xuan Wang, Meng-Yuan Zhang, Yu-Fan Wang, Si-Li Zhou, Jia-Lu Xu, Wen-Xuan Lin, Tian-Rui Ji, Ya-Dong Chen, Tao Lu, Nian-Guang Li, Zhi-Hao Shi
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Abstract

Mucosa-associated lymphoid tissue protein 1 (MALT1), a cysteine protease and the sole paracaspase in humans, plays a pivotal role in the survival and proliferation of NF-κB-dependent malignant cancers, particularly MALT lymphoma and diffuse large B-cell lymphoma (DLBCL). Dysregulated MALT1 activity is implicated in various malignancies, highlighting its importance as a therapeutic target. This Perspective provides an overview of MALT1’s structural and functional characteristics, summarizes recent advancements in small-molecule inhibitors and degraders targeting this protein, and discusses compound structures, structure–activity relationship (SAR) analyses, and biological activities. We aim to inform future research efforts to enhance the activity, selectivity, and pharmacological properties of MALT1-targeting compounds, establishing a foundational framework for drug development in this critical area of cancer therapy.

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MALT1抑制剂和降解剂:NF-κ b驱动型恶性肿瘤的治疗策略
粘膜相关淋巴组织蛋白1 (MALT1)是一种半胱氨酸蛋白酶,也是人类唯一的副半胱氨酸酶,在NF-κ b依赖性恶性肿瘤的生存和增殖中起关键作用,特别是MALT淋巴瘤和弥漫性大b细胞淋巴瘤(DLBCL)。MALT1活性失调与多种恶性肿瘤有关,突出了其作为治疗靶点的重要性。本展望综述了MALT1的结构和功能特征,总结了针对该蛋白的小分子抑制剂和降解剂的最新进展,并讨论了化合物结构、构效关系(SAR)分析和生物活性。我们的目标是为未来的研究工作提供信息,以增强malt1靶向化合物的活性、选择性和药理学性质,为癌症治疗这一关键领域的药物开发建立基础框架。
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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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