The structural requirements of histone deacetylase inhibitors: C4-modified SAHA analogs display dual HDAC6/HDAC8 selectivity
Abstract Histone deacetylase (HDAC) enzymes govern the post-translational acetylation state of lysine residues on protein substrates, leading to regulatory changes in cell function. Due to their role in cancers, HDAC proteins have emerged as promising targets for cancer treatment. Four HDAC inhibitors have been approved as anti-cancer therapeutics, including SAHA (Suberoylanilide hydroxamic acid, Vorinostat, Zolinza). SAHA is a nonselective HDAC inhibitor that targets most of the eleven HDAC isoforms. The nonselectivity of SAHA might account for its clinical side effects, but certainly limits its use as a chemical tool to study cancer-related HDAC cell biology. Herein, the nonselective HDAC inhibitor SAHA was modified at the C4 position of the linker to explore activity and selectivity. Several C4-modified SAHA analogs exhibited dual HDAC6/8 selectivity. Interestingly, ( R )-C4-benzyl SAHA displayed 520- to 1300-fold selectivity for HDAC6 and HDAC8 over HDAC1, 2, and 3, with IC 50 values of 48 and 27 nM with HDAC6 and 8, respectively. In cellulo testing of the inhibitors was consistent with the observed in vitro selectivity. Docking studies provided a structural rationale for selectivity. The C4-SAHA analogs represent useful chemical tools to understand the role of HDAC6 and HDAC8 in cancer biology and exciting lead compounds for targeting of both HDAC6 and HDAC8 in various cancers. Highlights Analogs of non-selective FDA-approved drug SAHA (Vorinostat) demonstrated selectivity for HDAC6 and 8 over HDAC1, 2, and 3. The best compound, ( R )-C4-benzyl SAHA, displayed IC 50 values of 48 and 27 nM with HDAC6 and HDAC8, respectively. ( R )-C4-benzyl SAHA maintained 520- to 1300-fold selectivity for HDAC6 and HDAC8. The HDAC6 selectivity of C4-benzyl SAHA was reproduced in cancer cells. Docking studies provided a structural rationale for the HDAC6/HDAC8 selectivity of C4-benzyl SAHA. Graphical abstract [DISPLAY OMISSION]
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