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Synthesis and biological evaluation of a tumor-selective degrader of PARP1
Chunlan Pu1, Shirui Wang2, Dan Luo2
1State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China; Medical Research Center, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, Sichuan 610031, China.
Abstract:
Poly (ADP-ribose) polymerase (PARP) inhibitors show potent antiproliferative activity in treatment with triple-negative breast cancer (TNBC) when combined with chemotherapeutic drugs. However, the emergence of safety issues and drug-resistance of PARP inhibitors prompt us to search for new strategies. It was proved that Proteolysis Targeting Chimeras (PROTACs) is more effective than traditional small molecule which can induce target proteins degradation rather than inhibition. In this article, based on the Olaparib derivatives and cereblon (CRBN) E3 ligase ligands, a series of PARP1 degraders, with linkers bearing different length and type were designed and synthesized. Among them, compound LB23 showed efficacious antiproliferative activity in various human cancer cells and can induce PARP1 protein degradation effectively. Moreover, LB23 showed 60-fold degradation selectivity in tumor cells with low degradation toxicity in normal cells. This study shows that the PROTAC tumor selectivity can be optimized by tuning the length and composition of the linker.
Insights
New Proteolysis Targeting Chimeras (PROTACs) effectively degrade Poly (ADP-ribose) polymerase 1 (PARP1) in cancer cells. Compound LB23 demonstrates potent antiproliferative activity and tumor selectivity, offering a promising alternative to traditional PARP inhibitors.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against triple-negative breast cancer (TNBC) but face safety and resistance challenges.
- Proteolysis Targeting Chimeras (PROTACs) offer a novel strategy by inducing target protein degradation, surpassing traditional inhibition.
- Developing new therapeutic agents is crucial to overcome limitations of existing cancer treatments.
Purpose of the Study:
- To design and synthesize novel Poly (ADP-ribose) polymerase 1 (PARP1) degraders using Proteolysis Targeting Chimeras (PROTACs) technology.
- To evaluate the antiproliferative activity and protein degradation efficacy of synthesized compounds in various human cancer cells.
- To investigate the tumor selectivity and potential toxicity of the developed PARP1 degraders.
Main Methods:
- Design and synthesis of a series of PARP1 degraders based on Olaparib derivatives and cereblon (CRBN) E3 ligase ligands.
- Utilized linkers with varying lengths and compositions to optimize PROTAC structure-activity relationships.
- Assessed antiproliferative activity and PARP1 protein degradation in human cancer cell lines.
Main Results:
- Compound LB23 exhibited significant antiproliferative effects across multiple human cancer cell lines.
- LB23 effectively induced Poly (ADP-ribose) polymerase 1 (PARP1) protein degradation.
- LB23 demonstrated a 60-fold degradation selectivity for tumor cells with minimal toxicity in normal cells, highlighting optimized PROTAC selectivity.
Conclusions:
- Proteolysis Targeting Chimeras (PROTACs) represent a viable and effective strategy for targeting Poly (ADP-ribose) polymerase 1 (PARP1) in cancer.
- The developed PARP1 degrader, LB23, shows potent efficacy and favorable tumor selectivity, suggesting its therapeutic potential.
- Tuning linker length and composition is a key strategy for optimizing PROTAC-mediated tumor selectivity and minimizing off-target toxicity.
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