Peptide‐Based 2‐Aminophenylamide Probes for Targeting Endogenous Class I Histone Deacetylase Complexes

Lysine deacetylases or histone deacetylases (HDACs) remove acetylation markers from numerous cellular proteins, thereby regulating their function and activity. Recently established peptide probes containing the HDAC‐trapping amino acid α‐aminosuberic acid ω‐hydroxamate (AsuHd) have been used to investigate the compositions of HDAC complexes in a site‐specific manner. Here we report the new HDAC‐trapping amino acid 2‐amino‐8‐[(2‐aminophenyl)amino]‐8‐oxooctanoic acid (AsuApa) and the utility of AsuApa‐containing probes for HDAC complex profiling on a proteome‐wide scale. Unlike AsuHd‐containing probes, AsuApa enriched only HDACs 1, 2, and 3 efficiently and was the most potent probe tested for capturing the last of these. These findings indicate that the inherent specificity of reported small‐molecule pimelic diphenylamide HDAC inhibitors is preserved in AsuApa and that this HDAC‐trapping amino acid represents a potent tool for investigating class I HDAC complexes.