Affiliation: | 1. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL, 60612 USA;2. Section of Hematology/Oncology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612 USA;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527 Egypt;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527 Egypt Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University, Alexandria, 21311 Egypt;5. Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612 USA;6. Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612 USA |
Abstract: | 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. |