Synthesis and analysis of small molecule libraries of HDAC inhibitors based on SAHA

Histone deacetylase (HDAC) proteins are transcription regulators linked to cancer. As a result, multiple small molecule HDAC inhibitors (HDACi) are in various phases of clinical trials as anti-cancer drugs, with suberoylanilide hydroxamic acid (SAHA) recently gaining FDA approval. The majority of HDAC inhibitors non-selectively influence the activities of eleven human HDAC isoforms, which are divided into distinct classes. Some HDAC inhibitors have been shown to be isoform-selective. Despite the advances in HDAC inhibitor design, many questions surrounding HDAC proteins and HDACi remain unanswered. Specifically, the role of each individual HDAC isoform remains unclear. More selective HDACi would provide information critical to HDAC isoform elucidation. Also, the structural requirements of HDAC inhibitors are not completely understood. Since HDACi are an important burgeoning class of anti-cancer drugs, a better understanding of their interactions with HDAC proteins are crucial to future therapeutic development. Therefore, to investigate the relationship between HDAC proteins and HDAC inhibitors, small molecule libraries of SAHA analogs were synthesized with a variety of substituents attached adjacent to the metal binding hydroxamic acid, adjacent to the anilide capping group, and directly on the hydroxamic 258 acid. The libraries were screened to help understand the structural requirements of HDAC inhibitors, develop a bump-hole study to elucidate individual HDAC protein function, and investigate isoform-selectivity. The biological data from the studies is important for the future design of HDAC inhibitors as anti-cancer therapeutics.