Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.
Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India.
Chem Biol Drug Des. 2024 Nov;104(5):e70009. doi: 10.1111/cbdd.70009.
Cereblon (CRBN), a member of the E3 ubiquitin ligase complex, has gained significant attention as a therapeutic target in cancer. CRBN regulates the degradation of various proteins in cancer progression, including transcription factors and signaling molecules. PROTACs (proteolysis-targeting chimeras) are a novel approach that uses the cell's degradation system to remove disease-causing proteins selectively. CRBN-dependent PROTACs work by tagging harmful proteins for destruction through the ubiquitin-proteasome system. This strategy offers several advantages over traditional protein inhibition methods, including the potential to overcome drug resistance. Recent progress in developing CRBN-based PROTACs has shown promising preclinical results in both hematologic malignancies and solid tumors. Additionally, CRBN-based PROTACs have enhanced our understanding of CRBN's role in cancer, potentially serving as biomarkers for patient stratification and predicting therapeutic responses. In this review, we delineate the mechanisms of action for CRBN-dependent PROTACs (CRBN-PROTACs), summarize recent advances in preclinical and clinical applications, and provide our perspective on future development.
cereblon (CRBN)，一种 E3 泛素连接酶复合物的成员，作为癌症治疗靶点引起了广泛关注。CRBN 调节癌症进展中各种蛋白质的降解，包括转录因子和信号分子。PROTACs（蛋白水解靶向嵌合体）是一种新的方法，利用细胞的降解系统有选择性地去除致病蛋白。CRBN 依赖性 PROTACs 通过泛素-蛋白酶体系统标记有害蛋白进行破坏。与传统的蛋白抑制方法相比，这种策略具有几个优势，包括克服耐药性的潜力。最近在开发基于 CRBN 的 PROTACs 方面取得的进展，在血液恶性肿瘤和实体瘤中均显示出有前景的临床前结果。此外，基于 CRBN 的 PROTACs 增强了我们对 CRBN 在癌症中的作用的理解，可能作为患者分层的生物标志物，并预测治疗反应。在这篇综述中，我们阐述了 CRBN 依赖性 PROTACs（CRBN-PROTACs）的作用机制，总结了最近在临床前和临床应用方面的进展，并对未来的发展提出了我们的看法。
