A highly HDAC6-selective inhibitor acts as a fluorescent probe

Area of Science:

• Biochemistry
• Chemical Biology
• Molecular Imaging

Background:

• Histone deacetylase 6 (HDAC6) is a therapeutic target for various diseases.
• Selective fluorescence imaging of HDAC6 is crucial for biological and pathological studies.
• Developing specific fluorescent probes for HDAC6 detection remains challenging.

Purpose of the Study:

• To design and synthesize novel fluorescent small-molecule inhibitors for selective HDAC6 detection.
• To evaluate the inhibitory activity and specificity of synthesized compounds against HDAC6.
• To assess the potential of these probes for cellular imaging and biological studies.

Main Methods:

• Synthesis of a series of naphthalimide-based fluorescent HDAC6 inhibitors.
• Structure-activity relationship (SAR) studies to identify potent and selective compounds.
• In vitro assays to determine inhibitory activity and specificity.
• Cellular imaging studies using fluorescent probes in cancer cell lines.

Main Results:

• Compound JW-1 demonstrated the highest inhibitory activity and specificity for HDAC6.
• JW-1 significantly increased alpha-tubulin acetylation, indicating HDAC6 inhibition.
• JW-1 exhibited activity against six different cancer cell lines.
• Photophysical and cellular imaging confirmed JW-1 as a fluorescent, cell-permeable HDAC6 inhibitor.

Conclusions:

• JW-1 is a highly fluorescent and specific small-molecule inhibitor of HDAC6.
• JW-1 can be effectively used for detecting HDAC6 in complex cellular environments.
• This probe holds potential for pathological and biological studies of HDAC6-related diseases.