Abstract
Histone deacetylase enzymes (HDACs) are potential targets for the treatment of cancer and other diseases, but it is challenging to design isoform-selective agents. In this work, we created new analogs of two established but non-selective HDAC inhibitors. We decorated the central linker chains of the molecules with specifically positioned fluorine atoms in order to control the molecular conformations. The fluorinated analogs were screened against a panel of 11 HDAC isoforms, and minor differences in isoform selectivity patterns were observed.
Highlights
Histone deacetylases (HDACs) are important enzymes whose functions include the regulation of gene expression [1]
Histones are post-translationally modified to contain acetyl groups on the ε-amino groups of some surface lysine residues; HDACs can catalyze the removal of these acetyl groups, thereby altering how tightly DNA winds around the histone, which in turn affects gene expression
HDAC isoforms that an aromatic capping group that binds at the surface of the enzyme; a linker ch have narrow tunnels (e.g., HDAC1–3) are challenging to target through variation of the penetrates through a tunnel leading into interior of the enzyme; linker
Summary
Histone deacetylases (HDACs) are important enzymes whose functions include the regulation of gene expression [1]. Figure 1) [3] and Scriptaid (7) [4] These inhibitors share three key features: an aromatic capping group that binds at the surface of the enzyme; a linker chain that penetrates through a tunnel leading into the interior of the enzyme; and a zinc-binding group that coordinates to a metal cofactor in the enzyme’s deeply buried active site. HDAC isoforms that an aromatic capping group that binds at the surface of the enzyme; a linker ch have narrow tunnels (e.g., HDAC1–3) are challenging to target through variation of the penetrates through a tunnel leading into interior of the enzyme; linker [8] because slim linkers usually fit not just thethe narrow-tunneled.
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