Gluetacs Therapeutics Co-reported PARP1 Degrader Demonstrating Superior Safety and Efficacy in BRCA-Deficient Tumors Published in Cell Death & Disease
ON：2024-12-23 TAGS：GLUETACS THERAPEUTICS
Recently, Gluetacs Therapeutics, in collaboration with the team of Fan Gaofeng from ShanghaiTech University, published an article titled “Minimizing DNA trapping while maintaining activity inhibition via selective PARP1 degrader” in the internationally renowned journal Cell Death & Disease. The article reports on a new generation of PROTAC degraders targeting the PARP1 protein, which inhibit the enzymatic activity of PARP1 while reducing the DNA trapping effect, and demonstrate safe and effective anti-tumor efficacy in BRCA-deficient tumors.
Fifgure 1
Poly (ADP-ribose) polymerase 1 (PARP1), a key enzyme in catalyzing poly (ADP-ribose)ylation reactions within eukaryotic cells, plays a central role in regulating protein post-translational modifications. Specifically, PARP1 is primarily involved in the repair process of single-strand DNA breaks. When PARP1 function is impaired, leading to ineffective repair of single-strand DNA damage, and the homologous recombination repair pathway is hindered due to BRCA gene mutations, this can lead to double-strand DNA breaks that also cannot be repaired, resulting in a synergistic lethal effect. This phenomenon provides a theoretical basis for synthetic lethality strategies, which are considered a highly promising new approach to cancer treatment. The research team developed PROTAC 180055, a PARP1-targeting degrader based on the PARP inhibitor rucaparib and the VHL E3 ubiquitin ligase ligand. This PROTAC can efficiently degrade PARP1 in various cells, and this degradation is reversible.
Figure 2 180055 degrades PARP1
Currently, clinically approved PARP inhibitors bind to the NAD-binding pocket of PARP1, trapping PARP1 at DNA damage sites. Due to the conservation of this binding pocket in the PARP family, PARP inhibitors often also target other members of the PARP family, causing some clinical side effects. To assess the specificity of 180055 for PARP1 degradation, the research team conducted quantitative proteomics analysis based on mass spectrometry in the T47D cell line, and the results showed that PROTAC 180055 could specifically degrade PARP1 without off-target effects.
Figure 3 180055 selectively degrades PARP1 among whole proteomics
Furthermore, in vitro experiments showed that 180055 could inhibit the growth of tumor cells carrying BRCA mutations without affecting the growth of normal cells. This indicates that 180055 is a potential PARP1 degradation molecule that warrants further exploration and validation in clinical trials.
Figure 4 180055 inhibits BRCA-mut tumor progression in CDX model
In summary, the research team has developed a new PARP1-targeting PROTAC degrader, 180055, which can efficiently degrade PARP1 and inhibit its enzymatic activity. This molecule has good specificity, no DNA trapping effects, and can effectively kill BRCA-mutated tumors while maintaining high safety.
Gluetacs, as the corresponding unit, has once again published an article in collaboration with academic institutions, further demonstrating the rich technical reserves and translational potential of the GlueTacs® platform, as well as its significant academic and commercial value.