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Structurally Diverse Histone Deacetylase Photoreactive Probes: Design, Synthesis, and Photolabeling Studies in Live Cells and Tissue
Author(s) -
Aboukhatwa Shaimaa M.,
Hanigan Thomas W.,
Taha Taha Y.,
Neerasa Jayaprakash,
Ranjan Rajeev,
ElBastawissy Eman E.,
Elkersh Mohamed A.,
ElMoselhy Tarek F.,
Frasor Jonna,
Mahmud Nadim,
McLachlan Alan,
Petukhov Pavel A.
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900114
Subject(s) - histone deacetylase , chemistry , histone deacetylase inhibitor , histone , histone deacetylase 2 , histone deacetylase 5 , computational biology , microbiology and biotechnology , combinatorial chemistry , biophysics , biochemistry , biology , dna
Histone deacetylase (HDAC) activity is modulated in vivo by post‐translational modifications and formation of multiprotein complexes. Novel chemical tools to study how these factors affect engagement of HDAC isoforms by HDAC inhibitors (HDACi) in cells and tissues are needed. In this study, a synthetic strategy to access chemically diverse photoreactive probes (PRPs) was developed and used to prepare seven novel HDAC PRPs 9 – 15 . The class I HDAC isoform engagement by PRPs was determined in biochemical assays and photolabeling experiments in live SET‐2, HepG2, HuH7, and HEK293T cell lines and in mouse liver tissue. Unlike the HDAC protein abundance and biochemical activity against recombinant HDACs, the chemotype of the PRPs and the type of cells were key in defining the engagement of HDAC isoforms in live cells. Our findings suggest that engagement of HDAC isoforms by HDACi in vivo may be substantially modulated in a cell‐ and tissue‐type‐dependent manner.