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Design, synthesis, and biological evaluation of HDAC6 inhibitors targeting L1 loop and serine 531 residue

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Author(s)
Sonam JhaJi Hyun KimMikyung KimAi-Han NguyenKhan Hashim AliSunil K GuptaSun You ParkEunyoung HaYoung Ho Seo
Keimyung Author(s)
Ha, Eun Young
Department
Dept. of Biochemistry (생화학)
Journal Title
Eur J Med Chem
Issued Date
2024
Volume
265
Keyword
EpigeneticsHistone deacetylase 6Lung cancerSmall molecule
Abstract
Histone deacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones, leading to the silencing of genes. Targeting specific isoforms of HDACs has emerged as a promising approach for cancer therapy, as it can overcome drawbacks associated with pan-HDAC inhibitors. HDAC6 is a unique HDAC isoform that deacetylates non-histone proteins and is primarily located in the cytoplasm. It also has two catalytic domains and a zinc-finger ubiquitin binding domain (Zf-UBD) unlike other HDACs. HDAC6 plays a critical role in various cellular processes, including cell motility, protein degradation, cell proliferation, and transcription. Hence, the deregulation of HDAC6 is associated with various malignancies. In this study, we report the design and synthesis of a series of HDAC6 inhibitors. We evaluated the synthesized compounds by HDAC enzyme assay and identified that compound 8g exhibited an IC50 value of 21 nM and 40-fold selective activity towards HDAC6. We also assessed the effect of compound 8g on various cell lines and determined its ability to increase protein acetylation levels by Western blotting. Furthermore, the increased acetylation of α-tubulin resulted in microtubule polymerization and changes in cell morphology. Our molecular docking study supported these findings by demonstrating that compound 8g binds well to the catalytic pocket via L1 loop of HDAC6 enzyme. Altogether, compound 8g represents a preferential HDAC6 inhibitor that could serve as a lead for the development of more potent and specific inhibitors.
Keimyung Author(s)(Kor)
하은영
Publisher
School of Medicine (의과대학)
Type
Article
ISSN
1768-3254
Source
https://www.sciencedirect.com/science/article/abs/pii/S0223523423010243
DOI
10.1016/j.ejmech.2023.116057
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/45472
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Biochemistry (생화학)
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