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APQ 通过调控 SETDB1 的活性改善亨廷顿病小鼠模型的异染色质凝聚、运动功能和神经病理学。

Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington's disease mouse model.

机构信息

Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.

Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, Republic of Korea.

出版信息

J Enzyme Inhib Med Chem. 2021 Dec;36(1):856-868. doi: 10.1080/14756366.2021.1900160.

DOI:10.1080/14756366.2021.1900160
PMID:33771089
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8008885/
Abstract

The present study describes evaluation of epigenetic regulation by a small molecule as the therapeutic potential for treatment of Huntington's disease (HD). We identified 5-allyloxy-2-(pyrrolidin-1-yl)quinoline (APQ) as a novel SETDB1/ESET inhibitor using a combined and cell based screening system. APQ reduced SETDB1 activity and H3K9me3 levels in a HD cell line model. In particular, not only APQ reduced H3K9me3 levels in the striatum but it also improved motor function and neuropathological symptoms such as neuronal size and activity in HD transgenic (YAC128) mice with minimal toxicity. Using H3K9me3-ChIP and genome-wide sequencing, we also confirmed that APQ modulates H3K9me3-landscaped epigenomes in YAC128 mice. These data provide that APQ, a novel small molecule SETDB1 inhibitor, coordinates H3K9me-dependent heterochromatin remodelling and can be an epigenetic drug for treating HD, leading with hope in clinical trials of HD.

摘要

本研究描述了小分子对表观遗传调控的评估，作为治疗亨廷顿病 (HD) 的治疗潜力。我们使用组合的 和 细胞基础筛选系统，鉴定出 5-丙烯氧基-2-(吡咯烷-1-基)喹啉 (APQ) 为一种新型 SETDB1/ESET 抑制剂。APQ 降低了 HD 细胞系模型中的 SETDB1 活性和 H3K9me3 水平。特别是，APQ 不仅降低了纹状体中的 H3K9me3 水平，而且还改善了运动功能和神经病理学症状，如神经元大小和活动，而毒性最小。使用 H3K9me3-ChIP 和全基因组测序，我们还证实 APQ 调节 YAC128 小鼠中的 H3K9me3 景观表观基因组。这些数据表明，APQ 是一种新型小分子 SETDB1 抑制剂，可协调 H3K9me 依赖性异染色质重塑，可作为治疗 HD 的表观遗传药物，为 HD 的临床试验带来希望。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/9007925a7bd0/IENZ_A_1900160_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/a1de20a821fe/IENZ_A_1900160_UF0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/f5fd9e601658/IENZ_A_1900160_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/ea9eeac7a04e/IENZ_A_1900160_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/3fa752541ba7/IENZ_A_1900160_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/a386f3d04d80/IENZ_A_1900160_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/2d81d8e59ea7/IENZ_A_1900160_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/7d7431aa3bdd/IENZ_A_1900160_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/f3de2e943e00/IENZ_A_1900160_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/34ccdefef7c5/IENZ_A_1900160_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/9007925a7bd0/IENZ_A_1900160_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/a1de20a821fe/IENZ_A_1900160_UF0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/f5fd9e601658/IENZ_A_1900160_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/ea9eeac7a04e/IENZ_A_1900160_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/3fa752541ba7/IENZ_A_1900160_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/a386f3d04d80/IENZ_A_1900160_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/2d81d8e59ea7/IENZ_A_1900160_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/7d7431aa3bdd/IENZ_A_1900160_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/f3de2e943e00/IENZ_A_1900160_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/34ccdefef7c5/IENZ_A_1900160_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/606b/8008885/9007925a7bd0/IENZ_A_1900160_F0008_C.jpg

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