A highly HDAC6-selective inhibitor acts as a fluorescent probe

Organic & Biomolecular Chemistry
Yi-Hsun HoChao-Wu Yu

Abstract

HDAC6 receives great attention because of its therapeutic potential for the treatment of various diseases. Selective fluorescence imaging for HDAC6 is important for its pathological and biological studies. However, specific detection of HDAC6 by using a fluorescent small molecule probe remains a great challenge. Herein, a series of fluorescent HDAC6-selective inhibitors incorporating a naphthalimide skeleton were designed and synthesized. A structure-activity relationship study identified that compound JW-1 had the greatest inhibitory activity and superior specificity against HDAC6. JW-1 could substantially increase α-tubulin acetylation and was active against a panel of six cancer cell lines. Photophysical characterization and cellular imaging of MDA-MB-231 cells demonstrated that JW-1 is a highly fluorescent, cell penetrable, small-molecule inhibitor of HDAC6 that can be used for the detection of HDAC6 in complex cellular environments.

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Citations

May 21, 2020·Chemical Communications : Chem Comm·Elley E RudebeckFrederick M Pfeffer
Dec 3, 2020·Frontiers in Oncology·Donglu WuDa Liu
Apr 29, 2021·Cell Chemical Biology·Anna SkwarskaEster M Hammond
Jun 20, 2021·Bioorganic & Medicinal Chemistry Letters·Sasha Padilla-ColeyFrederick M Pfeffer

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Methods Mentioned

BETA
acetylation
fluorescence microscopy
column chromatography
NMR
protein assay

Software Mentioned

PyMOL
AutoDock Vina
MGLtools
SwissPDBviewer
Elementar Vario EL
OriginPro
GraphPad Prism

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