Histone acetyltransferase inhibitors: An overview in synthesis, structure-activity relationship and molecular mechanism

Acetylation, a key component in post-translational modification regulated by HATs and HDACs, is relevant to many crucial cellular contexts in organisms. Based on crucial pharmacophore patterns and the structure of targeted proteins, HAT inhibitors are designed and modified for higher affinity and better bioactivity. However, there are still some challenges, such as cell permeability, selectivity, toxicity and synthetic availability, which limit the improvement of HAT inhibitors. So far, only few HAT inhibitors have been approved for commercialization, indicating the urgent need for more successful and effective structure-based drug design and synthetic strategies. Here, we summarized three classes of HAT inhibitors based on their sources and structural scaffolds, emphasizing on their synthetic methods and structure–activity relationships and molecular mechanisms, hoping to facilitate the development and further application of HAT inhibitors. [Display omitted] •Three classes of HAT inhibitors were summarized based on their sources and structural scaffolds.•The review focuses on synthetic approaches and modifications with biological results.•Overview of the protein active sites and mechanistic proposals.