A narrative review of proteolytic targeting chimeras (PROTACs): future perspective for prostate cancer therapy.
A narrative review of proteolytic targeting chimeras (PROTACs): future perspective for prostate cancer therapy.
复制标题
蛋白水解靶向嵌合体 (PROTAC) 的叙述性回顾：前列腺癌治疗的未来前景
DOI：
10.21037/tau-20-1357
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发表时间：
2021-03
影响因子：
2
通讯作者：
Shang Z
中科院分区：
文献类型：
--
作者：
Chen X;Shen H;Shao Y;Ma Q;Niu Y;Shang Z
蛋白水解-靶向嵌合体（Proteolysis-Targeting Chimeras，PROTAC）技术作为一种在蛋白质水平上化学敲除转录因子的策略，可以劫持泛素-蛋白酶体降解系统，启动细胞内泛素-蛋白酶体水解过程，从而降解蛋白质。过去，以转录因子为靶点的药物开发受到很大限制，甚至在历史上转录因子一直被视为“不可药靶点”。PROTAC技术以其独特的靶向设计突破了这一限制。经过几代技术创新，PROTAC日趋成熟，在包括前列腺癌（PCa）在内的靶向治疗领域不断取得突破，为抗肿瘤靶向药物的发展提供了新的策略。PROTAC具有现有小分子抑制剂的所有优点，易于口服给药，具有良好的细胞渗透性，并且与常规抑制剂相比具有更宽的靶向特征。PROTAC的缺点是非癌特异性，脱靶和缓释控制，由于其催化作用。一些雄激素受体（AR）和CDK 4/6降解剂已经推进了PCa治疗领域，鉴于这些降解剂在临床前和临床研究中的作用，该领域正在进一步改进。本文详细介绍了PROTAC的技术进展和面临的挑战，PCa的研究进展，以及PROTAC的发展前景。
Proteolysis-TArgeting Chimeras (PROTACs) technology, as a strategy to chemically knock down transcription factors at the protein levels, can hijack the ubiquitin-proteasome degradation system to initiate the intracellular ubiquitin-proteasome hydrolysis process to degrade proteins. In the past, the development of drugs that target transcription factors has been greatly restricted, and even historically transcription factors have been regarded as “undruggable targets”. PROTAC technology breaks through this limitation with its unique targeting design. With several generations of technical innovation, PROTACs have become more mature and continue to make breakthroughs in the field of targeted therapy including prostate cancer (PCa), with a new strategy for the development of anti-tumor targeted drugs. PROTACs have all the advantages of existing small molecule inhibitors, are easy to administer orally, have good cell permeability, and have wider targeting profiles compared to conventional inhibitors. The disadvantage of PROTACs is the noncancer specificity, off-target and sustained-release control, due to its catalytic role. Some androgen receptor (AR) and CDK4/6 degraders have advanced the field of PCa treatment, which is being further modified given the effects of these degraders in preclinical and clinical studies. This review summarizes in detail the technological progress and challenges that have been faced with PROTACs, the progress of research on PCa, and the prospective future of PROTACs development.