Recent advancements in cancer therapy have spotlighted targeted protein degradation as a promising approach to eliminate challenging, undruggable proteins implicated in various diseases. An innovative platform utilizing DNA aptamers to target E3 ligases, known as ZATACs, offers fresh hope for tackling these resilient proteins, including nucleolin, SOX2, and mutant p53.
Proteolysis-targeting chimeras (PROTACs) have emerged as groundbreaking therapeutic agents, but their effectiveness has often been hampered by the limited selection of E3 ligases available for development. Traditionally, the two most commonly employed E3 ligases have been cereblon (CRBN) and von Hippel-Lindau (VHL). Research indicates these ligases encounter resistance through various mechanisms, including mutations and downregulation of components within the ubiquitin ligase machinery. This has led to the necessity for alternative ligands to expand the scope of targeted protein degradation.
The recent study conducted by researchers at Tianjin Medical University introduces ZATACs, which incorporate aptamer-based constructs targeting the E3 ligase ZYG11B. The underlying goal was to realize highly effective, modular, and versatile pathways for targeted protein degradation. The authors have highlighted ZYG11B as it recognizes specific substrate proteins during cellular processes such as apoptosis.
Using the SELEX method, which allows for the specific selection of aptamers, the research team identified Apt#Z6, which selectively binds ZYG11B without interfering with its ligase activity. This advance marks the first application of aptamers directly targeting E3 ligases within PROTAC frameworks.
The versatility of the ZATAC platform is evident as it effectively eliminates various undruggable proteins. The study confirms Apt#Z6’s application led to significant degradation of proteins like nucleolin (NCL) and SRY-box transcription factor 2 (SOX2), both notorious for their challenging roles within cancer biology.
Importantly, to strengthen the delivery of these novel degradation agents, the researchers engineered trispecific ZATACs, termed 3WJ-ZATACs. By integrating additional aptamers capable of binding specific proteins overexpressed on cancer cells, these constructs demonstrated excellent tumor-specific distribution and the ability to achieve dual-target degradation.
During preclinical evaluations, ZATACs exhibited remarkable antitumor activities. For example, treatment with NCL-targeted ZATACs significantly suppressed tumor growth, documented through various assays, including colony formation and 3D tumor spheroid models. Further studies confirmed the mechanism of action, relying on the ZYG11B E3 ligase and ubiquitin-proteasome pathways.
The research clearly illustrated the efficiency of ZATAC, providing evidence for the potential use of this platform to target additional transcription factors classified as 'undruggable', including the p53-R175H mutant, commonly associated with various cancers.
This recent advancement not only broadens the available arsenal of E3 ligases but also opens new avenues for the discovery of others. ZATACs have been characterized as effective for selective and efficient intracellular delivery of molecular agents, streamlining the development of potent therapeutics deployed to combat aggressive malignancies.
Adopting aptamer ligands shows promise, especially concerning their stability, biocompatibility, and precise targeting capabilities. The shift toward applying ZATACs within clinical contexts reflects the growing consensus on their potential to revolutionize cancer therapy.
Collectively, the findings from this study establishes ZATAC as a modular platform, illuminating the path for innovative cancer treatments targeting traditionally difficult proteins. Further research aims to refine these approaches and explore their viability within human clinical trials.