Activity-Guided Design of HDAC11-Specific Inhibitors
| Autor: | Ji Cao, Hening Lin, Chengliang Zhu, Seth P. Miller, Se In Son |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Acylation 01 natural sciences Biochemistry Histone Deacetylases Article Serine Biological pathway 03 medical and health sciences Drug Discovery Humans Transferase chemistry.chemical_classification biology 010405 organic chemistry Drug discovery HDAC11 Rational design General Medicine 0104 chemical sciences Histone Deacetylase Inhibitors 030104 developmental biology Enzyme Histone chemistry Drug Design MCF-7 Cells biology.protein Molecular Medicine |
| Zdroj: | ACS Chem Biol |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.9b00292 |
| Popis: | Mammalian histone deacetylases (HDACs) are a class of enzymes that play important roles in biological pathways. Existing HDAC inhibitors target multiple HDACs without much selectivity. Inhibitors that target one particular HDAC will be useful for investigating the biological functions of HDACs and for developing better therapeutics. Here, we report the development of HDAC11-specific inhibitors using an activity-guided rational design approach. The enzymatic activity and biological function of HDAC11 have been little known, but recent reports suggest that it has efficient defatty-acylation activity and that inhibiting it could be useful for treating a variety of human diseases, including viral infection, multiple sclerosis, and metabolic diseases. Our best inhibitor, SIS17, is active in cells and inhibited the demyristoylation of a known HDAC11 substrate, serine hydroxymethyl transferase 2, without inhibiting other HDACs. The activity-guided design may also be useful for the development of isoform-specific inhibitors for other classes of enzymes. |
| Databáze: | OpenAIRE |
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