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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting
Xin-Yang Li1,2, De-Pu Wang1, Guo-Qing Lu1
1School of Pharmacy, China Medical University, Shenyang 110122, China.
Introduction:
The development of a new type of Thymidylate synthase (TS) inhibitor that could inhibit cancer cells' proliferation and anti-angiogenesis is of great significance for cancer's clinical treatment.
Objectives:
Our research hopes to develop a TS inhibitor that is more effective than the current first-line clinical treatment of pemetrexed (PTX) and provide a new reference for the clinical treatment of non-small cell lung cancer (NSCLC).
Methods:
We obtained a series of novel TS inhibitors by chemical synthesis. Moreover, TS assay and molecular docking to verify the target compound's inhibitory mode. Use MTT assay, colony-forming assay, flow cytometry, and western blot to verify the compound's inhibitory effect on cancer cell proliferation and its mechanism; and explore the compound's effect on angiogenesis in vitro and in vivo. Further, explore the hit compound's anti-cancer ability through the xenograft tumor model and the orthotopic cancer murine model.
Results:
A series of N-(3-(5-phenyl-1,3,4-oxadiazole-2-yl) phenyl)-2,4-dihydroxypyrimidine-5-sulfamide derivatives were synthesized as TS inhibitors for the first time. All target compounds significantly inhibited hTS enzyme activity and demonstrated significant antitumor activity against five cancer cell lines. Notably, 7f had a high selectivity index (SI) and unique inhibitory effects on eight NSCLC cells. In-depth research indicated that 7f could induce apoptosis by the mitochondrial pathway in A549 and PC-9 cells through the upregulation of wild-type P53 protein expression. Additionally, 7f was shown to inhibit angiogenesis in vitro and in vivo. In vivo studies, compared to PTX, 7f significantly inhibited tumor growth in A549 cell xenografts and had a higher therapeutic index (TGI). Moreover, 7f could prolong the survival of the orthotopic lung cancer murine model more effectively than PTX.
Conclusion:
The anti-angiogenic effect of 7f provides a new reference for the development of TS inhibitors and the clinical treatment of NSCLC.
Insights
A novel Thymidylate synthase (TS) inhibitor, compound 7f, demonstrates potent anti-cancer effects by inhibiting proliferation and angiogenesis. This new TS inhibitor shows promise for treating non-small cell lung cancer (NSCLC) more effectively than current treatments.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Development of novel Thymidylate synthase (TS) inhibitors is crucial for cancer treatment, targeting cell proliferation and angiogenesis.
- Existing treatments like pemetrexed (PTX) have limitations, necessitating more effective therapeutic agents for non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To synthesize and evaluate novel TS inhibitors with potential for enhanced efficacy compared to pemetrexed (PTX).
- To investigate the anti-proliferative and anti-angiogenic mechanisms of these novel compounds in NSCLC models.
Main Methods:
- Chemical synthesis of novel N-(3-(5-phenyl-1,3,4-oxadiazole-2-yl) phenyl)-2,4-dihydroxypyrimidine-5-sulfamide derivatives.
- In vitro assays including TS enzyme activity, molecular docking, MTT, colony formation, flow cytometry, and western blot.
- In vivo studies using xenograft and orthotopic lung cancer murine models, assessing anti-angiogenesis and therapeutic efficacy.
Main Results:
- Novel TS inhibitors were synthesized, with compound 7f exhibiting significant inhibition of hTS enzyme activity and potent antitumor activity across multiple cancer cell lines.
- Compound 7f demonstrated high selectivity and unique inhibitory effects on NSCLC cells, inducing apoptosis via the mitochondrial pathway and upregulating p53.
- 7f effectively inhibited angiogenesis in vitro and in vivo, outperforming pemetrexed (PTX) in tumor growth inhibition and survival prolongation in murine models.
Conclusions:
- Compound 7f represents a promising novel TS inhibitor with significant anti-proliferative and anti-angiogenic properties.
- The anti-angiogenic activity of 7f offers a new therapeutic strategy for NSCLC, providing a potential alternative to current treatments.
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