Chemotherapeutic strategy has been widely used for treating malignance by targeting irregular expressed or mutant proteins with small molecular inhibitors (SMIs) or monoclonal antibodies (mAbs). However, most intracellular proteins lack of active sites or antigens where SMIs or mAbs bind with, and are called as non-druggable targets for a long time. From the first year of this century, PROteolysis-TArgeting Chimeras (PROTACs) has emerged to be a promising approach for proteins, including those non-druggable ones, such as transcriptional factors and scaffold proteins. The first generation of peptide-based PROTACs adopts β-TrCP and VHL as E3 ligases, but the cellular permeability and chemical stability issues restrict their clinical application. The second generation of small molecule-based PROTACs adopts MDM2, VHL, IAPs and Cereblon as E3 ligases have been tensely studied. To date, the targets of PROTACs including those overexpressed oncogenic proteins such as ER, AR and BRDs, disease-relevant fusion proteins such as NPM/EML4-ALK and BCR-ABL, cancer-driven mutant proteins such as EGFR, kinases such as CDKs and RTKs. The major disadvantage of PROTACs is the noncancer specificity and relative higher toxicity, due to its catalytic role. To overcome this, we and other have recently developed several similar light-controllable PROTACs, termed as the third generation controllable PROTACs. The degradation of targets by those PROTACs can be triggered by UVA or visible light, providing a tool box for further PROTACs design. Here in this review, we introduce the historical milestones and prospective for further PROTACs development in clinical use.

通过使用小分子抑制剂 (SMI) 或单克隆抗体 (mAb) 靶向不规则表达或突变的蛋白质，化疗策略已被广泛用于治疗恶性肿瘤。然而，大多数细胞内蛋白质缺乏SMIs或mAbs结合的活性位点或抗原，长期以来被称为非药物靶点。从本世纪的第一年开始，蛋白水解-靶向嵌合体 (PROTACs) 已成为蛋白质的一种有前途的方法，包括那些不可成药的蛋白质，例如转录因子和支架蛋白。第一代肽基PROTACs采用β-TrCP和VHL作为E3连接酶，但细胞渗透性和化学稳定性问题限制了其临床应用。第二代小分子PROTACs采用MDM2、VHL、作为 E3 连接酶的 IAPs 和 Cereblon 已经得到了紧张的研究。迄今为止，PROTACs 的靶点包括那些过表达的致癌蛋白，如 ER、AR 和 BRD，疾病相关的融合蛋白，如 NPM/EML4-ALK 和 BCR-ABL，癌症驱动的突变蛋白，如 EGFR，激酶如 CDK和 RTK。由于其催化作用，PROTACs 的主要缺点是非癌症特异性和相对较高的毒性。为了克服这个问题，我们和其他人最近开发了几种类似的光可控 PROTAC，称为第三代可控 PROTAC。这些 PROTAC 对目标的降解可以由 UVA 或可见光触发，为进一步的 PROTAC 设计提供了一个工具箱。在这篇综述中，我们介绍了 PROTACs 在临床应用中进一步发展的历史里程碑和前景。