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As a new paradigm for targeting protein degraders, oligonucleotide-based PROTACs can be used not only as a research tool but also as a therapeutic tool to target DNA-binding proteins and inhibit cancer cell growth in vitro and in vivo for the effective treatment of diseases such as cancer.
As a leading CRO, BOC Sciences is able to provide oligonucleotide-based PROTACs development services. With a comprehensive and advanced platform, we are dedicated to the development of innovative targeted protein degradation technologies, providing our clients with research tools to help them achieve their new drug discovery objectives.
The PROTAC (proteolysis-targeting chimera) is a bifunctional molecule consisting of three parts: an E3 ligase-recruiting ligand, a target protein-binding ligand, and a Linker. Oligonucleotide-based PROTACs, a class of unconventional PROTACs, incorporate an oligonucleotide as a binding part to recognize the protein of interest.
Unlike classical PROTACs, which usually target disease-associated proteins with cytoplasmic structural domains containing binding sites, the development of oligonucleotide-based PROTACs has expanded the range of intracellular target proteins, such as DNA-binding proteins. In this case, unique DNA sequences serve as natural ligands for the targets.
Transcription factors (TFs) are DNA-binding proteins that interact with specific DNA sequences. TFs represent an important class of therapeutic targets and are drivers of many diseases, including cancer. Because TFs lack active or variable sites, they are difficult for conventional small molecule inhibitors to bind to them and have long been considered undruggable targets.
Fig. 1 Oligonucleotide-based PROTACs (Shao, 2021)
In 2021, TF-PROTACs consisting of DNA oligonucleotides linked to E3 ligase ligands by click reaction were reported to selectively degrade pathogenic TFs. The VHL-based TF-PROTACs: NF-κB-PROTAC and E2F-PROTAC, were effective in degrading endogenous cellular p65 and E2F1 proteins, respectively, and showed excellent anti-proliferative effects. In the same year, Crews' group reported oligoTRAFTACs targeting TFs. protein blotting experiments showed that oligoTRAFTACs successfully degraded two oncogenic transcription factors: c-Myc and brachyury.
Aptamers are single-stranded DNA or RNA oligonucleotides with unique three-dimensional structures that bind specifically to homologous molecular targets. Aptamers have the advantages of simple preparation, easy chemical modification, good stability, high specificity, and good in vivo safety. An aptamer-PROTAC conjugate (APC) have been reported in 2021, which consists of a PROTAC targeting BET and the aptamer AS1411 conjugated through a cleavable linker, showing enhanced anti-tumor effects compared to conventional PROTAC.
The development of oligonucleotide-based PROTACs is progressing rapidly, but is still in the early discovery stage. The instability and negative charge of oligonucleotides limit their entry into cells, and the rapid degradation of oligonucleotides may lead to unfavorable pharmacokinetics. More in-depth studies are needed to bring oligonucleotide-based PROTACs into clinical applications.
With decades of experience in targeted protein degradation, BOC Sciences keeps abreast of the cutting edge of PROTAC technology and provides customized services for the development of oligonucleotide-based PROTACs, utilizing innovative PROTAC technology to aid our clients' research and drug discovery.
Reference
* PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.
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