Transcription factors (TFs) play central roles in gene regulation and disease progression but have long been considered undruggable due to the absence of well-defined binding pockets and their reliance on protein–protein or protein–DNA interactions. Proteolysis-targeting chimeras (PROTACs) offer a novel strategy to overcome these limitations by inducing selective degradation of TFs via the ubiquitin–proteasome system. This review highlights recent advances in TF-targeting PROTACs, focusing on key oncogenic TFs such as androgen receptor (AR), estrogen receptor alpha (ERα), BRD4, c-Myc, and STAT family members. Strategies for ligand design—including small molecules, peptides, and nucleic acid-based elements—are discussed alongside the use of various E3 ligases such as VHL, CRBN, and IAP. Several clinically advanced PROTACs, including ARV-110 and ARV-471, demonstrate the therapeutic potential of this technology. Despite challenges in pharmacokinetics and E3 ligase selection, emerging data suggest that PROTACs can successfully target TFs, paving the way for new treatment strategies across oncology and other disease areas.
转录因子（TFs）在基因调控和疾病进展中发挥核心作用，但由于缺乏明确的结合口袋且依赖蛋白质-蛋白质或蛋白质-DNA相互作用，长期以来被视为不可成药靶点。蛋白水解靶向嵌合体（PROTACs）通过泛素-蛋白酶体系统诱导选择性降解转录因子，为突破这一局限提供了新策略。本综述聚焦靶向转录因子的PROTACs最新进展，重点探讨雄激素受体（AR）、雌激素受体α（ERα）、BRD4、c-Myc及STAT家族成员等关键致癌转录因子的靶向策略。文章系统讨论了小分子、多肽及核酸元件等配体设计方法，并分析了VHL、CRBN、IAP等多种E3连接酶的选用策略。以ARV-110和ARV-471为代表的临床阶段PROTACs验证了该技术的治疗潜力。尽管在药代动力学和E3连接酶选择方面仍存挑战，最新研究表明PROTACs能有效靶向转录因子，为肿瘤及其他疾病领域开辟了新的治疗路径。
Targeting the Undruggable: Recent Progress in PROTAC-Induced Transcription Factor Degradation
肿瘤(癌症)患者之家