Minimizing DNA trapping while maintaining activity inhibition via selective PARP1 degrader

Area of Science:

• Biochemistry and Molecular Biology
• Cancer Therapeutics
• Drug Discovery

Background:

• Poly (ADP-ribose) polymerase 1 (PARP1) is crucial for DNA repair and a target in cancer therapy.
• Existing PARP1 inhibitors face challenges due to DNA trapping and off-target effects.
• There is a need for improved PARP1-targeted therapies with better safety profiles.

Purpose of the Study:

• To develop a novel therapeutic strategy targeting PARP1 using protein degradation technology.
• To synthesize and evaluate a Proteolysis Targeting Chimera (PROTAC) molecule for PARP1 degradation.
• To assess the efficacy and safety of the PROTAC molecule in preclinical cancer models.

Main Methods:

• Synthesis of a PROTAC molecule (180055) combining a Rucaparib-based moiety with a VHL ligand.
• Evaluation of PARP1 degradation and enzyme inhibition in vitro.
• Assessment of DNA trapping effects and off-target activities.
• In vitro and in vivo studies on tumor cell killing in BRCA-mutated models and impact on normal cells.

Main Results:

• The PROTAC molecule 180055 efficiently and selectively degraded PARP1.
• PARP1 enzyme activity was inhibited without significant DNA trapping.
• 180055 demonstrated selective killing of BRCA-mutated tumor cells.
• Minimal impact on normal cell growth was observed both in vitro and in vivo.

Conclusions:

• The synthesized PROTAC molecule 180055 effectively degrades PARP1 with high efficacy and safety.
• 180055 represents a promising new therapeutic candidate for cancers with homologous recombination deficiencies, such as BRCA-mutated tumors.
• Further clinical investigation of 180055 is warranted.