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Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)
Zhimin Zhang1, Xinyue Chang1, Chixiao Zhang1
1Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, P. R. China.
Abstract:
Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.
Insights
Researchers developed a novel PROTAC molecule that effectively degrades Poly(ADP-ribose) polymerase-1 (PARP-1), inhibiting cancer cell proliferation and migration. This new chemical probe offers a promising strategy for cancer therapy by targeting PARP-1 knockdown.
Area of Science:
- Molecular Biology
- Oncology
- Medicinal Chemistry
Background:
- Poly(ADP-ribose) polymerase-1 (PARP-1) is a key DNA repair enzyme and a validated cancer therapeutic target, particularly effective in BRCA1/2-mutated cancers.
- Existing PARP-1 inhibitors are approved for breast, ovarian, and prostate cancers, but proteolysis targeting chimaeras (PROTACs) offer a novel degradation-based strategy.
Purpose of the Study:
- To design, synthesize, and evaluate a novel PROTAC molecule for targeted degradation of PARP-1.
- To investigate the anti-cancer effects of the developed PROTAC, specifically compound 2, in relevant cancer cell lines.
Main Methods:
- Design and synthesis of a PROTAC (compound 2) by conjugating the PARP-1 inhibitor olaparib with the cereblon (CRBN) ligand lenalidomide.
- Evaluation of compound 2's efficacy in SW620 cells, assessing PARP-1 degradation, anti-proliferation, apoptosis induction, cell cycle arrest, and migration inhibition.
Main Results:
- Compound 2 effectively induced Poly(ADP-ribose) polymerase-1 (PARP-1) degradation in SW620 cancer cells.
- PARP-1 degradation by compound 2 resulted in significant anti-proliferation effects, apoptosis, cell cycle arrest, and inhibition of cancer cell migration.
Conclusions:
- The developed PROTAC molecule (compound 2) represents a potent chemical probe for achieving PARP-1 knockdown.
- This study validates PROTACs as a promising therapeutic strategy for targeting PARP-1 in cancer treatment.
