Chen Xuanrong, Shen Haishan, Shao Yi, Ma Qianwang, Niu Yuanjie, Shang Zhiqun
Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
Urology Development, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
Transl Androl Urol. 2021 Feb;10(2):954-962. doi: 10.21037/tau-20-1357.
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.
蛋白酶靶向嵌合体（PROTACs）技术作为一种在蛋白质水平化学敲低转录因子的策略，可劫持泛素-蛋白酶体降解系统，启动细胞内泛素-蛋白酶体水解过程以降解蛋白质。过去，靶向转录因子的药物开发受到极大限制，甚至在历史上转录因子一直被视为“不可成药靶点”。PROTAC技术凭借其独特的靶向设计突破了这一限制。经过几代技术创新，PROTACs已变得更加成熟，并在包括前列腺癌（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开发提供了新策略。PROTACs具备现有小分子抑制剂的所有优点，易于口服给药，具有良好的细胞通透性，与传统抑制剂相比具有更广泛的靶向谱。PROTACs的缺点是由于其催化作用导致的非癌症特异性、脱靶和缓释控制问题。一些雄激素受体（AR）和CDK4/6降解剂推动了PCa治疗领域的发展，鉴于这些降解剂在临床前和临床研究中的效果，该领域正在进一步改进。本文详细综述了PROTACs所面临的技术进展和挑战、PCa的研究进展以及PROTACs开发的未来前景。
