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The ups and downs of Poly(ADP-ribose) Polymerase-1 inhibitors in cancer therapy-Current progress and future direction
Yue Zhao1, Liu-Xia Zhang1, Ting Jiang2
1Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, PR China.
Abstract:
Poly(ADP-ribose) Polymerase 1 (PARP1), one of the most investigated 18 membered PARP family enzymes, is involved in a variety of cellular functions including DNA damage repair, gene transcription and cell apoptosis. PARP1 can form a PARP1(ADP-ribose) polymers, then bind to the DNA damage gap to recruit DNA repair proteins, and repair the break to maintain genomic stability. PARP1 is highly expressed in tumor cells, so the inhibition of PARP1 can block DNA repair, promote tumor cell apoptosis, and exert antitumor activity. To date, four PARP1 inhibitors namely olaparib, rucaparib, niraparib and talazoparib, have been approved by Food and Drug Administration (FDA) for treating ovarian cancer and breast cancer with BRCA1/2 mutation. These drugs have showed super advantages over conventional chemotherapeutic drugs with low hematological toxicity and slowly developed drug resistance. In this article, we summarize and analyze the structure features of PARP1, the biological functions and antitumor mechanisms of PARP1 inhibitors. Importantly, we suggest that establishing a new structure-activity relationship of developed PARP1 inhibitors via substructural searching and the matched molecular pair analysis would accelerate the process in finding more potent and safer PARP1 inhibitors.
Insights
Poly(ADP-ribose) Polymerase 1 (PARP1) inhibitors block tumor cell DNA repair, promoting apoptosis. Further analysis of PARP1 inhibitors will accelerate the development of more effective and safer antitumor treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Poly(ADP-ribose) Polymerase 1 (PARP1) is crucial for DNA repair and genomic stability.
- PARP1 is highly expressed in tumor cells, making it a target for cancer therapy.
- PARP1 inhibitors block DNA repair, leading to tumor cell apoptosis and antitumor activity.
Purpose of the Study:
- To summarize and analyze the structural features, biological functions, and antitumor mechanisms of PARP1 inhibitors.
- To explore strategies for developing more potent and safer PARP1 inhibitors.
- To establish new structure-activity relationships for PARP1 inhibitors.
Main Methods:
- Literature review and analysis of PARP1 structure and function.
- Summary of biological functions and antitumor mechanisms of PARP1 inhibitors.
- Exploration of substructural searching and matched molecular pair analysis for structure-activity relationship (SAR) development.
Main Results:
- Four PARP1 inhibitors (olaparib, rucaparib, niraparib, talazoparib) are FDA-approved for BRCA1/2 mutated ovarian and breast cancers.
- These inhibitors offer advantages over conventional chemotherapy, including lower toxicity and slower resistance development.
- Analysis suggests that substructural searching and matched molecular pair analysis can refine SAR for PARP1 inhibitors.
Conclusions:
- PARP1 inhibitors represent a significant advancement in cancer therapy, particularly for BRCA-mutated cancers.
- Further investigation into SAR is essential for designing next-generation PARP1 inhibitors.
- Developing more potent and safer PARP1 inhibitors holds promise for improved cancer treatment outcomes.
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