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Updated: Jun 11, 2025
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
Discovery of dual-targeted molecules based on Olaparib and Rigosertib for triple-negative breast cancer with
Zhikun Liu1, Shining Mao1, Lumei Dai2
1Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an 223003, China.
Abstract:
PARP inhibitors (PARPis) demonstrate significant potential efficacy in the clinical treatment of BRCA-mutated triple-negative breast cancer (TNBC). However, a majority of patients with TNBC do not possess BRCA mutations, and therefore cannot benefit from PARPis. Previous studies on multi-targeted molecules derived from PARPis or disruptors of RAF-RAF pathway have offered an alternative approach to develop novel anti-TNBC agents. Hence, to broaden the application of PARP inhibitors for TNBC patients with wild-type BRCA, a series of dual-targeted molecules were constructed via integrating the key pharmacophores of Olaparib (Ola) and Rigosertib into a single entity. Subsequent studies exhibited that the resulting compounds 13a-14c obtained potential anti-proliferative activity against BRCA-defected or wild-type TNBC cells. Among them, an optimal compound 13b showed good inhibitory activity toward PARP-1, displayed approximately 34-fold higher inhibitory activity than that of Ola in MDA-MB-231 cells, and exerted multi-functional mechanisms to induce apoptosis. Moreover, 13b displayed superior antitumor efficacy (TGI, 61.3 %) than the single administration of Ola (TGI, 38.5 %), 11b (TGI, 51.8 %) or even their combined administration (TGI, 56.7 %), but did not show significant systematic toxicity. These findings suggest that 13b may serve as a potential candidate for BRCA wild-type TNBC.
Insights
New dual-targeted molecules combining Olaparib and Rigosertib show promise for treating BRCA wild-type triple-negative breast cancer (TNBC). Compound 13b demonstrates potent anti-tumor activity and induces apoptosis, offering a potential new therapeutic strategy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- PARP inhibitors (PARPis) are effective for BRCA-mutated triple-negative breast cancer (TNBC).
- Most TNBC patients lack BRCA mutations, limiting PARPi benefit.
- Targeting alternative pathways like RAF-RAF is an approach for novel anti-TNBC agents.
Purpose of the Study:
- To develop novel dual-targeted molecules for BRCA wild-type TNBC.
- To integrate pharmacophores of Olaparib (PARPi) and Rigosertib (RAF-RAF pathway disruptor).
- To evaluate anti-proliferative activity and therapeutic potential in TNBC models.
Main Methods:
- Synthesis of dual-targeted compounds integrating Olaparib and Rigosertib pharmacophores.
- In vitro anti-proliferative assays against BRCA-defected and wild-type TNBC cells.
- In vivo evaluation of antitumor efficacy and toxicity of optimal compounds.
Main Results:
- Compounds 13a-14c exhibited anti-proliferative activity against TNBC cells.
- Optimal compound 13b showed potent PARP-1 inhibition and induced apoptosis.
- 13b demonstrated superior antitumor efficacy (TGI 61.3%) compared to Olaparib and combination therapies, with no significant toxicity.
Conclusions:
- Compound 13b is a promising candidate for treating BRCA wild-type TNBC.
- Dual-targeting strategy offers a potential therapeutic avenue for a broader TNBC patient population.
- Further investigation of 13b for BRCA wild-type TNBC is warranted.
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