Gupta Priyanka, Dutta Sumit, Kumar Prashant, Kaushik Monika, Ashique Sumel, Bhowmick Mithun
Department of Pharmacology, Sanaka Educational Trust, Durgapur, 713212, West Bengal, India.
School of Pharmaceutical Sciences, University of Science and Technology, Meghalaya, 793101, India.
Curr Drug Discov Technol. 2025 Feb 26. doi: 10.2174/0115701638324854250218053353.
Targeted Protein Degradation (TPD) offers a solution, eliminating disease-related proteins and overcoming challenges associated with unintended toxicity and lack of precision. PROTACs (Proteolysis Targeting Chimeras) represent an innovative strategy for the specific degradation of tar-get proteins through the UPS (Ubiquitin-Proteasome System). In comparison to conventional protein inhibitor medications, PROTAC offers advantages in terms of efficacy, selectivity, and the ability to overcome drug resistance in cancer treatment, contributing novel perspectives to the field of anti-cancer drug discovery. Proteins play vital roles in an organism's health, and misfolded contributes to diseases like neurodegenerative disorders and cancer. Cells maintain protein balance through quality control systems, primarily the UPS and autophagy. Protac, a Targeted Protein Degradation (TPD) strategy, utilizes UPS, employing small molecules to induce targeted protein degradation. PROTAC exhibits promise in preclinical studies and clinical trials for diverse cancers. Notable examples in-clude breast cancer, where PROTAC targets CDK4/6 (cyclin-dependent kinase) and Estrogen Recep-tors (ER), prostate cancer, addressing Androgen Receptor (AR) degradation, hematologic malignan-cies, focusing on AURORA-A and CDKs, and NSCLC (Non-Small-Cell Lung Cancer), targeting Estimated Glomerular Filtration Rate (EGFR), and KRAS. Despite their potential, PROTAC faces challenges, including compensatory protein expression in response to targeted therapies. This com-prehensive review explores recent advancements in PROTAC and related technologies, emphasizing the mechanisms and structures of PROTAC and their applications in proteins targeting cancer.
靶向蛋白降解(TPD)提供了一种解决方案,可消除与疾病相关的蛋白质,并克服与意外毒性和缺乏精准性相关的挑战。PROTACs(蛋白酶靶向嵌合体)代表了一种通过泛素-蛋白酶体系统(UPS)特异性降解靶蛋白的创新策略。与传统的蛋白抑制剂药物相比,PROTAC在疗效、选择性以及克服癌症治疗中的耐药性方面具有优势,为抗癌药物发现领域提供了新的视角。蛋白质在生物体健康中起着至关重要的作用,而错误折叠会导致神经退行性疾病和癌症等疾病。细胞通过质量控制系统,主要是UPS和自噬来维持蛋白质平衡。Protac是一种靶向蛋白降解(TPD)策略,利用UPS,采用小分子诱导靶向蛋白降解。PROTAC在多种癌症的临床前研究和临床试验中显示出前景。显著的例子包括乳腺癌,其中PROTAC靶向细胞周期蛋白依赖性激酶4/6(CDK4/6)和雌激素受体(ER);前列腺癌,解决雄激素受体(AR)降解问题;血液系统恶性肿瘤,聚焦极光激酶A(AURORA-A)和细胞周期蛋白依赖性激酶(CDK);以及非小细胞肺癌(NSCLC),靶向表皮生长因子受体(EGFR)和KRAS。尽管PROTAC具有潜力,但也面临挑战,包括对靶向治疗的补偿性蛋白表达。这篇综述探讨了PROTAC及相关技术的最新进展,强调了PROTAC的作用机制、结构及其在癌症靶向蛋白中的应用。