PARP Degrader Development

Poly(ADP-ribose) polymerase-1 (PARP1) is a crucial enzyme involved in various cellular processes, including DNA repair, cell signaling, and gene expression regulation. As such, the development of effective PARP1 modulators, including inhibitors and degraders, has become a significant focus in the field of drug discovery. At Alfa Cytology, our team of world-class scientists is dedicated to advancing the frontiers of cancer research and treatment.

Introduction to PARP Degrader

Poly(ADP-ribose) polymerase (PARP) is an important enzyme involved in various cellular processes, including DNA repair, cell signaling, and gene expression regulation. The development of PARP1 degraders based on PROTAC (Proteolysis Targeting Chimera) technology is an active area of research in targeted protein degradation strategies.

Fig. 1 A PARP1 PROTAC as a novel strategy against PARP inhibitor resistance via promotion of ferroptosis in p53-positive breast cancer. (Li G., et al. 2022)

PROTACs are heterobifunctional molecules that consist of three main components:

• A specific ligand that binds to the target protein of interest (PARP1 in this case).
• A ligand that binds to an E3 ubiquitin ligase, such as pomalidomide, thalidomide, or lenalidomide.
• A variable linker unit that connects the two ligands.

PARP Degrader Development

PROTACs using olaparib, rucaparib, and niraparib derivatives have been developed and tested in cancer and non-cancer cells. They exhibit improved cytotoxicity compared to conventional inhibitors and have a broader use beyond BRCA mutant cancers. Among them, PROTAC using niraparib and MDM2 ligand exhibited PARP1 degradation and increased PARP cleavage in MDA-MB-231 breast cancer cells. Interestingly, iRucaparib-AP6 does not induce PARP1 capture or cell death in cardiomyocytes. Non-capturing PARP degraders are promising for the treatment of diseases associated with PARP activation (e.g., ischemia-reperfusion injury or neurodegenerative diseases) because they do not induce genotoxicity or cell death.

Our Services

At Alfa Cytology, we are committed to advancing the field of targeted protein degradation and providing our clients with state-of-the-art solutions. Our team of experienced scientists and skilled technicians is dedicated to supporting the development of innovative PARP degraders and other targeted therapeutics.

• PROTAC PARP Development

Design and Synthesis of PROTAC Molecules

In Vitro and In Vivo Efficacy Assessments

Analytical Characterization and Quality Control

Evaluation of PARP Degradation Potency and Selectivity

Optimization of Pharmacokinetic and Metabolic Properties

Customized Project Management and Regulatory Support

• Hydrophobic Tagged PARP Inhibitor Development

Rational Design of Hydrophobic Tags and Linkers

Evaluation of Target Protein Degradation Potency and Selectivity

Cellular and Animal Model-Based Efficacy and Safety Assessments

Synthesis and Chemical Optimization of Hydrophobic-Tagged Compounds

In Vitro and In Vivo Pharmacokinetic and Metabolic Profiling

Customized Project Management and Regulatory Support

By leveraging our expertise in PARP biology, medicinal chemistry, and preclinical development, Alfa Cytology is well-equipped to assist our clients in navigating the complex landscape of PARP1 degrader development and bringing these promising therapeutic candidates closer to the clinic. To learn more about our PARP degrader development capabilities or to discuss your specific research and development needs, please don't hesitate to contact us.

For research use only. Not intended for any clinical use.