Structural and Functional Landscape of FAD-Dependent Histone Lysine Demethylases for New Drug Discovery
Structural and Functional Landscape of FAD-Dependent Histone Lysine Demethylases for New Drug Discovery
复制标题
用于新药发现的 FAD 依赖性组蛋白赖氨酸脱甲基酶的结构和功能景观
DOI：
10.1021/acs.jmedchem.2c01324
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发表时间：
2022-12-20
影响因子：
7.3
通讯作者：
Yu, Bin
中科院分区：
文献类型：
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作者：
Song, Yihui;Wang, Shu;Yu, Bin
靶向黄素腺嘌呤二核苷酸（FAD）依赖性组蛋白赖氨酸去甲基化酶LSD家族的小分子已显示出对各种疾病的治疗前景。目前正在研究9种靶向LSD家族的经典脱甲基酶依赖性功能的临床候选药物用于治疗癌症、神经退行性疾病等。此外，靶向LSD的非催化功能也代表了治疗人类疾病的新兴策略。在这个视角中，我们提供了LSD家族的完整结构和功能景观以及不同类型的LSD抑制剂的作用模式，包括天然产物，肽和合成化合物，旨在为新的LSD抑制剂的设计揭示新的可药用空间。特别地，我们首先根据它们独特的结合模式将这些抑制剂分为三种类型。此外，还简要讨论了针对LSD的脱甲基酶非依赖性功能的策略。这一观点可能有利于发现新的LSD抑制剂，用于探测LSD生物学和/或治疗人类疾病。
Small molecules targeting the flavin adenine dinucleotide (FAD)-dependent histone lysine demethylase LSD family have displayed therapeutic promise against various diseases. Nine clinical candidates targeting the classic demethylase-dependent functions of the LSD family are currently being investigated for treating cancers, neurodegenerative diseases, etc. Moreover, targeting noncatalytic functions of LSDs also represents an emerging strategy for treating human diseases. In this Perspective, we provide full structural and functional landscape of the LSD family and action modes of different types of LSD inhibitors including natural products, peptides, and synthetic compounds, aiming to reveal new druggable space for the design of new LSD inhibitors. Particularly, we first classify these inhibitors into three types based on their unique binding modes. Additionally, the strategies targeting the demethylase-independent functions of LSDs are also briefly discussed. This Perspective may benefit the discovery of new LSD inhibitors for probing LSD biology and/or treating human diseases.