Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou, Zhejiang 311121, China.
Recent Pat Anticancer Drug Discov. 2020;15(1):32-48. doi: 10.2174/1574892815666200217125419.
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.
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.
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.
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.
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.
许多人类疾病都与 HDACs 的失调有关。HDAC6 不仅对组蛋白蛋白具有去乙酰化酶活性，而且对非组蛋白蛋白如α-微管蛋白、HSP90、皮质蛋白和过氧化物还原酶也具有去乙酰化酶活性。近年来，HDAC6 的这些独特功能引起了药物化学界的极大关注。因此，人们投入了大量精力开发选择性 HDAC6 抑制剂，以期最大限度地减少泛 HDAC 抑制引起的副作用。
本综述旨在分析支架的结构特征，为对此领域感兴趣的人提供有用的信息，并激发新抑制剂的未来设计。
专利检索的主要工具是 SciFinder。所有专利均从以下网站检索：世界知识产权组织（WIPO®）、美国专利商标局（USPTO®）、Espacenet®和 Google Patents。本综述涵盖的专利年限为 2016 年至 2019 年。
根据 ZBG 的结构，将来自 17 家公司/学术机构的 36 项专利分为三类：羟肟酸、1,3,4-噁二唑和 1,2,4-噁二唑。ZBG 通过连接子与帽基团相连。帽基团可以容忍不同的官能团，包括酰胺、脲、磺酰胺、磺胺等。帽基团似乎调节了 HDAC6 对其他 HDAC 亚型的选择性。
选择性靶向 HDAC6 而不是其他亚型具有双重优势：它最大限度地提高了药理作用，最大限度地减少了泛 HDAC 抑制剂所看到的副作用。近年来，许多小分子选择性 HDAC6 抑制剂已进入临床研究。我们预计在不久的将来，选择性 HDAC6 抑制剂将被批准为治疗药物。
