PARP-1 Degradation for PARP-Related Diseases

Project Summary/Abstract This trans-disciplinary research proposal focuses on developing a novel class of PROteolysis TArgeting Chimeras (PROTACs) aimed at degrading Poly (ADP-ribose) polymerase-1 (PARP-1) activity in diseased human cells. PARP-1, one of the most abundant nuclear proteins, plays a pivotal role in responding to cellular stress, particularly DNA damage, through both enzymatic and scaffolding functions. Its enzymatic activity involves poly (ADP-ribosyl)ation (PARylation) of itself and key downstream substrates in the DNA damage response (DDR) pathway, facilitating the recruitment of DNA repair factors. Once PARylated, PARP-1 dissociates from DNA, allowing normal cellular processes to resume. Dysregulation of PARP-1 is implicated in various diseases, including neurodegenerative disorders (e.g., Alzheimer’s, Parkinson’s), inflammatory conditions (e.g., arthritis, multiple sclerosis, colitis), and several cancers, making it a high-priority target for therapeutic intervention. While PARP-1 inhibitors (PARPi) have achieved clinical success, with four FDA-approved for oncology, their mechanism frequently results in PARP-1 trapping at DNA repair sites, leading to cytotoxicity in normal cells. Moreover, resistance to PARPi remains a significant clinical hurdle. To address these challenges, this proposal aims to develop a new class of PARP-1 degraders that downregulate PARP-1 activity, effectively mimicking genetic ablation. Our approach involves designing a focused library of PROTACs utilizing highly selective, single- digit nanomolar PARP-1 inhibitors based on a novel benzoimidazole-4-carboxamide chemotype, coupled with cereblon E3 ligase ligands (Aim 1). These PROTACs will be evaluated in cellular models to confirm their time- and dose-dependent efficacy in degrading PARP-1 (Aim 2). Preliminary data support the feasibility of this strategy. In addition to advancing the field of targeted protein degradation, this project will offer valuable hands-on research experience in medicinal chemistry, computational modeling, enzymology, and cell biology to both undergraduate and graduate students. Moreover, successful outcomes from this collaboration will enhance the research capacity and scientific environment at Queens College.