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WXJ-202, a novel Ribociclib derivative, exerts antitumor effects against breast cancer through CDK4/6
Jing Ji1, Wenwen Liu1, Yuxin Xu1
1Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China.
Abstract:
Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulatory proteins in the cell division and proliferative cycle in humans. They are overactive in many malignant tumors, particularly in triple-negative breast cancer (TNBC). Inhibition of CDK4/6 targets can have anti-tumor effects. Here, we designed and synthesized a novel derivative of Ribociclib that could affect CDK4/6, named WXJ-202. This study aimed to investigate the effects of compound WXJ-202 on proliferation, apoptosis, and cell cycle arrest in human breast cancer cell lines and their molecular mechanisms. We assayed cell viability with methyl thiazolyl tetrazolium (MTT) assay. Clone formation, migration, and invasion ability were assayed by clone formation assay, wound healing assay, and transwell invasion assay. The effect of compound WXJ-202 on apoptosis and cell cycle was detected by flow cytometry analysis. Western blotting was performed to detect the expression of proteins related to the CDK4/6-Rb-E2F pathway. The anti-cancer effects were studied in vivo transplantation tumor models. WXJ-202 was shown to inhibit cell proliferation, colony formation, migration, and invasion, as well as induce apoptosis and cycle arrest in breast cancer cells. The levels of proteins related to the CDK4/6-Rb-E2F pathway, such as CDK4, CDK6, and p-Rb, were decreased. Finally, studies had shown that compound WXJ-202 exhibited significant anti-tumor activity in transplantation tumor models. In this research, the compound WXJ-202 was shown to have better anti-tumor cell proliferative effects and could be used as a potential candidate against TNBC tumors.
Insights
A novel compound, WXJ-202, effectively inhibits triple-negative breast cancer (TNBC) cell proliferation and induces apoptosis. This CDK4/6 inhibitor shows significant anti-tumor activity, making it a promising candidate for TNBC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cyclin-dependent kinases 4 and 6 (CDK4/6) are crucial regulators of cell division and are often overactive in cancers, including triple-negative breast cancer (TNBC).
- Targeting CDK4/6 offers a therapeutic strategy for inhibiting tumor growth.
Purpose of the Study:
- To design and synthesize a novel CDK4/6 inhibitor, WXJ-202, based on Ribociclib.
- To investigate the anti-cancer effects of WXJ-202 on breast cancer cell lines and elucidate its molecular mechanisms.
- To evaluate the in vivo anti-tumor efficacy of WXJ-202.
Main Methods:
- Cell viability, proliferation, colony formation, migration, and invasion were assessed using MTT, clone formation, wound healing, and Transwell assays.
- Apoptosis and cell cycle arrest were analyzed by flow cytometry.
- Protein expression related to the CDK4/6-Rb-E2F pathway was determined via Western blotting. In vivo efficacy was studied in transplantation tumor models.
Main Results:
- WXJ-202 significantly inhibited breast cancer cell proliferation, colony formation, migration, and invasion.
- The compound induced apoptosis and cell cycle arrest in cancer cells.
- Expression of CDK4, CDK6, and p-Rb proteins was reduced, indicating modulation of the CDK4/6-Rb-E2F pathway. Significant anti-tumor activity was observed in vivo.
Conclusions:
- WXJ-202 demonstrates potent anti-proliferative and pro-apoptotic effects against breast cancer cells.
- The compound effectively targets the CDK4/6-Rb-E2F pathway.
- WXJ-202 exhibits significant anti-tumor activity and represents a potential therapeutic candidate for TNBC.
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