Hwang, Yu Jin Hyeon, Seung Jae Kim, Younghee Lim, Sungsu Lee, Min Young Kim, Jieun ASHWINI, MACHHINDRA LONDHE Gotina, Lizaveta Kim, Yunha Pae, Ae Nim Cho, Yong Seo Seong, Jihye Seo, Hyemyung Kim, Yun Kyung Choo, Hyunah Ryu, Hoon Min, Sun-Joon 2024-01-19T15:34:40Z 2024-01-19T15:34:40Z 2021-09-02 2021-01 1475-6366 https://pubs.kist.re.kr/handle/201004/117620 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 in silico and in vitro 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. English Taylor & Francis Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington's disease mouse model Article 10.1080/14756366.2021.1900160 1 Journal of Enzyme Inhibition and Medicinal Chemistry, v.36, no.1, pp.856 - 868 Journal of Enzyme Inhibition and Medicinal Chemistry 36 1 856 868 Y scie scopus 000634049000001 2-s2.0-85103420933 Biochemistry & Molecular Biology Chemistry, Medicinal Biochemistry & Molecular Biology Pharmacology & Pharmacy Article Huntington&#8217 s disease medium spiny neuron motor function SETDB1