<br>调节 LSD1 的新疗法策略,Acta Pharmaceutica Sinica B

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调节 LSD1 的新疗法策略
Acta Pharmaceutica Sinica B ( IF 14.7 ) Pub Date : 2024-01-10 , DOI: 10.1016/j.apsb.2024.01.005
Meng Li ₁ , Mengge Dai ₁ , Bing Cheng ₁ , Shaotong Li ₁ , Enhui Guo ₁ , Junwei Fu ₁ , Ting Ma _{1,

2} , Bin Yu _{1,

2,

3,

4,

5}

Affiliation

组蛋白甲基化在表观遗传修饰中调节染色质结构和基因转录中起着至关重要的作用。赖氨酸特异性去甲基化酶 1 (LSD1) 是第一个被鉴定的组蛋白去甲基化酶，在各种疾病中普遍过度表达。 LSD1失调与癌症、病毒感染、神经退行性疾病等密切相关，使其成为一个有前景的治疗靶点。多种LSD1抑制剂和两种小分子降解剂（UM171和BEA-17）已进入临床阶段。 LSD1 可以去除组蛋白 3 赖氨酸 4 或赖氨酸 9（H3K4 或 H3K9）处的甲基，从而导致转录抑制或激活。虽然 LSD1 在转录调控中的作用已明确，但研究表明 LSD1 也可以受到其他因素的动态调控。例如，LSD1 的表达或活性可以通过与 LSD1 形成转录辅阻遏物复合物的许多蛋白质来调节。此外，一些转录后修饰和细胞代谢物也可以调节LSD1表达或其去甲基酶活性。因此，在这篇综述中，我们将系统地总结转录辅阻遏物复合物、各种翻译后修饰和代谢物中涉及的蛋白质如何作为LSD1活性的调节因子。

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Strategies that regulate LSD1 for novel therapeutics

Histone methylation plays crucial roles in regulating chromatin structure and gene transcription in epigenetic modifications. Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, is universally overexpressed in various diseases. LSD1 dysregulation is closely associated with cancer, viral infections, and neurodegenerative diseases, etc., making it a promising therapeutic target. Several LSD1 inhibitors and two small-molecule degraders (UM171 and BEA-17) have entered the clinical stage. LSD1 can remove methyl groups from histone 3 at lysine 4 or lysine 9 (H3K4 or H3K9), resulting in either transcription repression or activation. While the roles of LSD1 in transcriptional regulation are well-established, studies have revealed that LSD1 can also be dynamically regulated by other factors. For example, the expression or activity of LSD1 can be regulated by many proteins that form transcriptional corepressor complexes with LSD1. Moreover, some post-transcriptional modifications and cellular metabolites can also regulate LSD1 expression or its demethylase activity. Therefore, in this review, we will systematically summarize how proteins involved in the transcriptional corepressor complex, various post-translational modifications, and metabolites act as regulatory factors for LSD1 activity.

更新日期：2024-01-10

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