从“不可成药”到“斩草除根” 蛋白药物能否为癌症治疗带来曙光？

Core Viewpoint - Cancer remains a significant challenge in modern society, with a new revolutionary technology, targeted protein degradation, offering potential solutions for previously "undruggable" targets [1][2]. Group 1: Targeted Protein Degradation Technology - PROTAC (Proteolysis Targeting Chimeras) is an emerging therapeutic strategy that targets and degrades proteins associated with cancer and other diseases, with approximately 3,000 proteins linked to these conditions, but only about 700 are currently druggable [2][3]. - PROTAC operates by briefly binding to the target protein and directing it to the cell's natural degradation system, allowing for efficient and sustained effects with minimal dosage [2][3]. - The mechanism of PROTAC is described as "capture-release," which allows for the complete elimination of pathogenic proteins, addressing multiple disease-causing pathways [2]. Group 2: Clinical Trials and Developments - Since 2019, at least 30 PROTACs have entered clinical trials, primarily targeting cancer, with three PROTACs currently in Phase III trials for breast cancer, prostate cancer, and leukemia [3][4]. - The first PROTAC to enter Phase III trials is vepdegestrant, developed by Arvinas and Pfizer, which has shown to extend disease-free survival in patients with a specific breast cancer mutation compared to standard anti-estrogen therapies [3]. - Other PROTACs in Phase III trials target the androgen receptor in metastatic prostate cancer and the BTK enzyme in chronic lymphocytic leukemia, addressing issues of drug resistance in advanced cancers [3]. Group 3: Limitations and Future Prospects - Despite the promising potential of PROTACs, they face limitations, such as difficulty in targeting membrane-embedded proteins and the risk of unintended degradation of other proteins [4]. - The first approval of a PROTAC is anticipated to be a significant milestone, likely targeting an already druggable cancer-related protein, while true breakthroughs would involve previously untargeted proteins [4]. - Molecular glue is emerging as another potential protein degradation agent, which operates differently from PROTAC by altering the surface of ubiquitin ligases to facilitate protein degradation without direct binding [5].