Rodrigues Daniel Alencar, Roe Andrew, Griffith Darren, Chonghaile Tríona Ní
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Department of Chemistry, Royal College of Surgeons in Ireland, Dublin, Ireland.
Curr Top Med Chem. 2022 Mar 4;22(5):408-424. doi: 10.2174/1568026621666211015092047.
Due to developments in modern chemistry, previously uundruggable substrates are now targetable thanks to selective degradation using the ubiquitin-proteasomal degradation system. PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules designed specifically to degrade target proteins. They are of significant interest to industry and academia as they are highly specific and can target previously undruggable target proteins from transcription factors to enzymes. More than 15 degraders are expected to be evaluated in clinical trials by the end of 2021. Herein, we describe recent advances in the design and development of PROTAC-mediated degradation of histone deacetylases (HDACs). PROTAC-mediated degradation of HDACs can offer some significant advantages over direct inhibition, such as the use of substoichiometric doses and the potential to disrupt enzyme-independent HDAC function. We discuss the potential implication of the degradation of HDACs in comparison with HDAC knockout studies. Along with the selection of HDAC inhibitors and E3 ligase ligands for the design of PROTACs. The potential utility of HDAC PROTACs in various disease pathologies from cancer to inflammation to neurodegeneration is driving the interest in this field.
由于现代化学的发展，借助泛素-蛋白酶体降解系统进行选择性降解，以前难以成药的底物现在可以成为靶点。蛋白酶靶向嵌合体（PROTACs）是专门设计用于降解靶蛋白的异双功能分子。它们受到了工业界和学术界的极大关注，因为它们具有高度特异性，能够靶向从转录因子到酶等以前难以成药的靶蛋白。预计到2021年底，将有超过15种降解剂进入临床试验评估。在此，我们描述了PROTAC介导的组蛋白去乙酰化酶（HDACs）降解在设计和开发方面的最新进展。与直接抑制相比，PROTAC介导的HDACs降解具有一些显著优势，例如使用亚化学计量剂量以及有可能破坏不依赖酶的HDAC功能。我们讨论了与HDAC基因敲除研究相比，HDACs降解的潜在意义。同时还介绍了用于PROTACs设计的HDAC抑制剂和E3连接酶配体的选择。HDAC PROTACs在从癌症到炎症再到神经退行性变等各种疾病病理中的潜在应用价值，正推动着该领域的研究热潮。
