Department of Chemistry, School of Advanced Sciences (SAS), Vellore Institute of Technology (VIT), Vellore 632014, India; Drug Discovery Unit (DDU), Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology (VIT), Vellore 632014, India.
Drug Discovery Unit (DDU), Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology (VIT), Vellore 632014, India; School of Biosciences and Technology (SBST), Vellore Institute of Technology (VIT), Vellore 632014, India.
Pharmacol Ther. 2024 Nov;263:108725. doi: 10.1016/j.pharmthera.2024.108725. Epub 2024 Sep 24.
Targeted protein degradation (TPD) has emerged as a prominent and vital strategy for therapeutic intervention of cancers and other diseases. One such approach involves the exploration of proteolysis targeting chimeras (PROTACs) for the selective elimination of disease-causing proteins through the innate ubiquitin-proteasome pathway. Due to the unprecedented achievements of various PROTAC molecules in clinical trials, researchers have moved towards other physiological protein degradation approaches for the targeted degradation of abnormal proteins, including lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), molecular glue degraders, and other derivatives for their precise mode of action. Despite numerous advantages, these molecules face challenges in solubility, permeability, bioavailability, and potential off-target or on-target off-tissue effects. Thus, an urgent need arises to direct the action of these degrader molecules specifically against cancer cells, leaving the proteins of non-cancerous cells intact. Recent advancements in TPD have led to innovative delivery methods that ensure the degraders are delivered in a cell- or tissue-specific manner to achieve cell/tissue-selective degradation of target proteins. Such receptor-specific active delivery or nano-based passive delivery of the PROTACs could be achieved by conjugating them with targeting ligands (antibodies, aptamers, peptides, or small molecule ligands) or nano-based carriers. These techniques help to achieve precise delivery of PROTAC payloads to the target sites. Notably, the successful entry of a Degrader Antibody Conjugate (DAC), ORM-5029, into a phase 1 clinical trial underscores the therapeutic potential of these conjugates, including LYTAC-antibody conjugates (LACs) and aptamer-based targeted protein degraders. Further, using bispecific antibody-based degraders (AbTACs) and delivering the PROTAC pre-fused with E3 ligases provides a solution for cell type-specific protein degradation. Here, we highlighted the current advancements and challenges associated with developing new tumour-specific protein degrader approaches and summarized their potential as single agents or combination therapeutics for cancer.
靶向蛋白降解（TPD）已成为治疗癌症和其他疾病的一种重要策略。其中一种方法是探索蛋白水解靶向嵌合体（PROTAC），通过天然的泛素-蛋白酶体途径选择性地消除致病蛋白。由于各种 PROTAC 分子在临床试验中取得了前所未有的成就，研究人员已经转向其他生理蛋白降解方法，以靶向降解异常蛋白，包括溶酶体靶向嵌合体（LYTAC）、自噬靶向嵌合体（AUTAC）、自噬体连接化合物（ATTEC）、分子胶降解剂和其他衍生物，以实现其精确的作用模式。尽管这些分子具有许多优势，但它们在溶解度、通透性、生物利用度以及潜在的脱靶或靶外组织效应方面仍面临挑战。因此，迫切需要将这些降解剂分子的作用专门导向癌细胞，而使非癌细胞的蛋白质保持完整。TPD 的最新进展带来了创新的递药方法，确保降解剂以细胞或组织特异性的方式递送到细胞或组织中，以实现靶蛋白的细胞/组织选择性降解。通过将 PROTAC 与靶向配体（抗体、适体、肽或小分子配体）或纳米载体偶联，可以实现 PROTAC 的受体特异性主动递药或基于纳米的被动递药。这些技术有助于实现 PROTAC 有效载荷精确递送到靶位。值得注意的是，Degrader Antibody Conjugate（DAC）ORM-5029 成功进入 1 期临床试验，突显了这些偶联物的治疗潜力，包括 LYTAC-抗体偶联物（LAC）和基于适体的靶向蛋白降解剂。此外，使用双特异性抗体基降解剂（AbTAC）并递送至与 E3 连接酶预融合的 PROTAC，为细胞类型特异性蛋白降解提供了一种解决方案。在这里，我们强调了开发新的肿瘤特异性蛋白降解方法的最新进展和挑战，并总结了它们作为单一药物或联合治疗癌症的潜力。
