Targeted therapies for cancer are typically small molecules or monoclonal antibodies that act by inhibiting the activity of specific proteins that drive tumor growth. Although many of these drugs are effective in cancer patients, the response is often not durable because tumor cells develop resistance to the drugs. Another limitation of this strategy is that not all oncogenic driver proteins are “druggable” enzymes or receptors with activities that can be inhibited. Here we describe an alternative approach to targeted therapy that is based on co-opting the cellular quality-control machinery—the ubiquitin-proteasome system—to remove specific cancer-causing proteins from the cell. We first discuss examples of existing cancer drugs that work by degrading specific proteins and then review recent progress in the rational design and preclinical testing of small molecules that induce selective degradation of specific target proteins.
癌症靶向治疗通常采用小分子药物或单克隆抗体，通过抑制驱动肿瘤生长的特定蛋白质活性发挥作用。尽管这些药物对癌症患者有效，但肿瘤细胞常通过产生耐药性导致疗效难以持久。该策略的另一局限在于，并非所有致癌驱动蛋白都属于可被抑制活性的"可成药"酶或受体。本文阐述了一种替代性靶向治疗策略，即通过利用细胞质控机制——泛素-蛋白酶体系统——清除细胞内特定的致癌蛋白。我们首先探讨现有抗癌药物通过降解特定蛋白质发挥作用的实例，继而综述选择性诱导靶蛋白降解的小分子药物的理性设计及临床前研究新进展。
肿瘤(癌症)患者之家