Novel Selective Histone Deacetylase 6 (HDAC6) Inhibitors: A Patent Review (2016-2019)

Abstract

Background: Many human diseases are associated with dysregulation of HDACs. HDAC6 exhibits deacetylase activity not only to histone protein but also to non-histone proteins such as α- tubulin, HSP90, cortactin, and peroxiredoxin. These unique functions of HDAC6 have gained significant attention in the medicinal chemistry community in recent years. Thus a great deal of effort has devoted to developing selective HDAC6 inhibitors for therapy with the hope to minimize the side effects caused by pan-HDAC inhibition. Objective: The review intends to analyze the structural feature of the scaffolds, to provide useful information for those who are interested in this field, as well as to spark the future design of the new inhibitors. Methods: The primary tool used for patent searching is SciFinder. All patents are retrieved from the following websites: the World Intellectual Property Organization (WIPO®), the United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents. The years of patents covered in this review are between 2016 and 2019. Results: Thirty-six patents from seventeen companies/academic institutes were classified into three categories based on the structure of ZBG: hydroxamic acid, 1,3,4-oxadiazole, and 1,2,4-oxadiazole. ZBG connects to the cap group through a linker. The cap group can tolerate different functional groups, including amide, urea, sulfonamide, sulfamide, etc. The cap group appears to modulate the selectivity of HDAC6 over other HDAC subtypes. Conclusion: Selectively targeting HDAC6 over other subtypes represents two fold advantages: it maximizes the pharmacological effects and minimizes the side effects seen in pan-HDAC inhibitors. Many small molecule selective HDAC6 inhibitors have advanced to clinical studies in recent years. We anticipate the approval of selective HDAC6 inhibitors as therapeutic agents in the near future.

Role of Selective Histone Deacetylase 6 Inhibitor ACY-1215 in Cancer and Other Human Diseases

“…Due to adverse toxicity such as fatigue, diarrhea, and thrombocytopenia, their clinical application is limited ( Falkenberg and Johnstone, 2014 ; Minucci and Pelicci, 2006 ). To develop potentially less toxic and more effective treatments, studies on selective HDACs inhibitors are gradually deepening ( Zhao et al, 2021 ; He et al, 2020 ). Chemical modification of the cap group allows for isomer selective HDACs inhibitors ( Krämer et al, 2014 ).…”

Targeting Epigenetic Regulatory Enzymes for Cancer Therapeutics: Novel Small-Molecule Epidrug Development

“…Epigenomic alterations mediated by epigenetic regulatory enzymes have a profound effect on many hallmarks of cancer, including malignant self-renewal, differentiation blockade, evasion of cell death, and tissue invasiveness ( 167 ). The anticancer roles of inhibitors targeting epigenetic regulatory enzymes provide attractive targets for novel drugs, even if enzymes that selectively regulate the target genes are not well known ( 168 ). Some HATis, HDACis, and DNMTis have been approved as anticancer epidrugs.…”

Discovery of 2-Phenylquinoline-4-Carboxylic Acid Derivatives as Novel Histone Deacetylase Inhibitors

“…Inhibition of HDACs has been extensively studied in the development of anticancer drugs. The discovery of selective HDAC inhibitors has emerged as a hotspot in the epigenetic therapy ( He et al, 2020 ). Selective inhibitors are considered to be promising for cancer treatment by targeting a particular tumor type or a specific mechanism in the tumorigenesis.…”