This set of anticancer compounds selectively degrades or inhibits cancer-related histone deacetylase proteins. These proteins are commonly overexpressed in various cancer types, and class I histone deacetylase proteins activate oncogenes that cause tumor formation, cancer progression, and treatment resistance. In addition to their role in cancers, when dysregulated, these proteins can cause the onset of inflammatory and metabolic disorders. Histone deacetylase inhibitors are promising anticancer therapies but have previously been prone to undesirable off-target activity.
Researchers at the University of Florida have identified first-in-class benzoylhydrazide-containing compounds that inhibit or destroy specific proteins by acting as a molecular glue that targets class I histone deacetylase complexes. One of these compounds has shown in vivo safety and potent anticancer activities in breast cancer models.
Treatment of cancer and other human diseases by targeting class I histone deacetylase-containing complexes for proteasome degradation
Benzoylhydrazide compounds that selectively inhibit or degrade cancer-related proteins by targeting class I histone deacetylase complexes. These compounds specifically target histone deacetylase-associated lysine-specific demthylase1 (LSD1) and the scaffolding protein (CoREST1) for proteasomal degradation. One compound, SR-4370, shows excellent in vivo safety and potent anticancer efficacy in multiple in vivo cancer models.