Design, Synthesis, and Biological Evaluation for First GPX4 and CDK Dual Inhibitors
Jiangmin Zhu1, Yuxing Cai1, Min Kong1
1Jiangsu Key Laboratory of Bioactive Natural Product Research, State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
Abstract:
The coexistence of ferroptosis and other modes of death has great advantages in the treatment of cancers. A series of glutathione peroxidase 4 (GPX4) and cyclin-dependent kinase (CDK) dual inhibitors were designed and synthesized, given the synergistic anticancer effect of ML162 (GPX4 inhibitor) in combination with indirubin-3'-oxime (IO) (CDK inhibitor). Compound B9 exhibited the highest potential cytotoxic activity against all four cell lines and displayed excellent inhibitory activity against GPX4 (IC50 = 542.5 ± 0.9 nM) and selective inhibition of CDK 4/6 (IC50 = 191.2 ± 8.7, 68.1 ± 1.4 nM). Mechanism research showed that B9 could simultaneously induce ferroptosis and arrest cells at the G1 phase in both MDA-MB-231 cells and HCT-116 cells. Compared with ML162 and IO, B9 showed much stronger cancer cell growth inhibition in vivo. These results proved that developing potent GPX4/CDK dual inhibitors is a promising strategy for the malignant cancer therapy.
Insights
Researchers developed a dual inhibitor targeting ferroptosis and cell cycle progression for cancer therapy. Compound B9 effectively inhibits glutathione peroxidase 4 (GPX4) and cyclin-dependent kinases (CDKs), showing potent anticancer activity in vitro and in vivo.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Combining ferroptosis and other cell death pathways offers therapeutic advantages for cancer treatment.
- Synergistic anticancer effects observed between GPX4 inhibitors (ML162) and CDK inhibitors (indirubin-3'-oxime).
Purpose of the Study:
- To design and synthesize novel dual inhibitors targeting both GPX4 and CDKs.
- To evaluate the anticancer potential of these dual inhibitors.
Main Methods:
- Synthesis of a series of GPX4 and CDK dual inhibitors.
- In vitro cytotoxicity assays against multiple cancer cell lines.
- Enzyme inhibition assays for GPX4 and CDK 4/6.
- Cell cycle analysis and ferroptosis induction studies.
- In vivo efficacy studies in mouse models.
Main Results:
- Compound B9 demonstrated significant cytotoxic activity across four cell lines.
- B9 potently inhibited GPX4 (IC50 = 542.5 nM) and selectively CDK 4/6 (IC50 = 191.2/68.1 nM).
- B9 induced both ferroptosis and G1 phase arrest in MDA-MB-231 and HCT-116 cells.
- B9 exhibited superior in vivo cancer growth inhibition compared to single-target inhibitors.
Conclusions:
- Dual inhibition of GPX4 and CDKs is a promising strategy for cancer therapy.
- Compound B9 represents a potent dual inhibitor with significant therapeutic potential.
- Further development of GPX4/CDK dual inhibitors could lead to effective malignant cancer treatments.
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