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Updated: Sep 19, 2025
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
Design and Synthesis of PARP/CDK6 Dual-Target Inhibitors Modulating of Wnt/β-Catenin Signaling Pathway for the
Yonglei Zhang1, Fucheng Yin1, Zhongwen Luo1
1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
Abstract:
Poly(ADP-ribose) polymerase (PARP) inhibitors have been approved and marketed for the treatment of BRCA-mutated breast and ovarian cancers. Recent studies have demonstrated that cyclin-dependent kinase 4/6 (CDK4/6) inhibitors can induce defects in homologous recombination (HR) repair, thereby sensitizing breast cancer cells with HR proficiency to PARP inhibitors through a synthetic lethal mechanism. Here, we report the rational design and synthesis of a potent dual PARP/CDK6 inhibitor 11, which was identified through SAR studies. Compound 11 effectively induces excessive DNA damage and apoptosis in MDA-MB-231 cells, while maintaining robust inhibitory activity against both PARP and CDK6. Additionally, 11 demonstrates excellent antitumor efficacy and antimetastatic properties, with no evident toxicity or side effects observed. Further investigations revealed that 11 could inhibit tumor cell proliferation by modulating the Wnt/β-catenin signaling pathway. In summary, these findings highlight the potential therapeutic advantages of 11, coded with KWZY-11, in treating BRCA wild-type tumors.
Insights
A new dual inhibitor (KWZY-11) targets both PARP and CDK6, showing promise for treating BRCA wild-type breast cancers by inducing DNA damage and apoptosis with minimal side effects.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Poly(ADP-ribose) polymerase (PARP) inhibitors are approved for BRCA-mutated cancers.
- Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors induce homologous recombination (HR) repair defects, sensitizing HR-proficient cells to PARP inhibitors via synthetic lethality.
Purpose of the Study:
- To design and synthesize a potent dual inhibitor targeting both PARP and CDK6.
- To evaluate the therapeutic potential of the novel compound in BRCA wild-type tumors.
Main Methods:
- Structure-activity relationship (SAR) studies were employed for rational drug design.
- Compound 11 was synthesized and evaluated for its inhibitory activity against PARP and CDK6.
- In vitro and in vivo studies assessed antitumor efficacy, antimetastatic properties, and toxicity.
Main Results:
- Compound 11 demonstrated potent dual inhibition of PARP and CDK6.
- It effectively induced DNA damage and apoptosis in MDA-MB-231 cells.
- Compound 11 exhibited significant antitumor efficacy and antimetastatic activity with no observed toxicity.
Conclusions:
- The dual PARP/CDK6 inhibitor KWZY-11 (compound 11) shows therapeutic potential for BRCA wild-type tumors.
- It acts by inducing DNA damage, apoptosis, and modulating the Wnt/β-catenin pathway.
- KWZY-11 presents a promising strategy for overcoming resistance to current therapies.
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