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A novel quinoid-based CDC25 phosphatase inhibitor against human lung adenocarcinoma across different models
Tsung-Ching Lai1, Iin Narwanti2, Bidyadhar Sethy3
1Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Abstract:
Cell division cycle 25 (CDC25) phosphatase is a key cell cycle regulator whose overexpression is linked to tumor malignancy and poor prognosis. Its inhibition suppresses cancer cell growth and induces cell death, making it a promising therapeutic target. In this study, we aimed to develop novel CDC25 inhibitors with therapeutic potential. Using NSC663284 (compound 1) as the lead compound, we synthesized and screened derivatives based on cell-viability assays. Among five cancer types tested, lung cancer emerged as the most suitable model. Notably, compound 6 exhibited the most potent inhibitory activity against CDC25 phosphatase. A clinical data analysis of a Clinical Proteome Tumor Analysis Consortium (CPTAC) or The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset revealed that high expression levels of CDC25A and CDC25C were associated with a poor prognosis and were positively correlated with the T status. Moreover, CDC25C expression was positively associated with lymph node metastasis. In vitro, compound 6 exhibited stronger cytotoxicity and pro-apoptotic effects than compound 1, and significantly suppressed LUAD cell colony formation, migration, and invasion. In vivo, both compounds reduced tumor growth in H1975 xenograft mice, with compound 6 inducing more extensive tumor cell death. Furthermore, compound 6 also inhibited LUAD patient-derived organoid (PDO) growth. Combination studies of compound 6 with chemotherapeutic drugs indicated that compound 6 exhibited synergistic effects with those drugs in inhibiting the growth of LUAD cells. In conclusion, compound 6 is a promising lead compound for CDC25 inhibition and warrants further investigation as a potential therapeutic agent for LUAD treatment.
Insights
Novel compound 6 effectively inhibits CDC25 phosphatase, showing potent anti-cancer effects against lung adenocarcinoma (LUAD). This CDC25 inhibitor demonstrates therapeutic potential by suppressing tumor growth and enhancing chemotherapy efficacy in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Cell division cycle 25 (CDC25) phosphatases are crucial cell cycle regulators implicated in tumor malignancy.
- CDC25 overexpression correlates with poor prognosis, making CDC25 a significant therapeutic target in cancer.
- Inhibition of CDC25 suppresses cancer cell proliferation and induces apoptosis, highlighting its therapeutic relevance.
Purpose of the Study:
- To develop novel CDC25 inhibitors with potential therapeutic applications.
- To evaluate the efficacy of synthesized CDC25 inhibitors, particularly compound 6, in lung cancer models.
- To investigate the clinical relevance of CDC25 expression in lung adenocarcinoma (LUAD) patient data.
Main Methods:
- Synthesis and screening of CDC25 inhibitor derivatives based on lead compound NSC663284 (compound 1).
- Evaluation of compound efficacy using cell-viability assays, in vitro functional assays (cytotoxicity, apoptosis, colony formation, migration, invasion), and in vivo xenograft mouse models.
- Analysis of clinical data from CPTAC and TCGA-LUAD datasets to correlate CDC25 expression with prognosis and clinicopathological features.
Main Results:
- Compound 6 demonstrated potent CDC25 phosphatase inhibitory activity and superior cytotoxicity and pro-apoptotic effects compared to compound 1.
- Clinical data analysis revealed high CDC25A and CDC25C expression is linked to poor prognosis and advanced tumor stage in LUAD.
- Compound 6 significantly suppressed LUAD cell growth, migration, invasion, and xenograft tumor progression, and showed synergistic effects with chemotherapy.
Conclusions:
- Compound 6 is a highly promising lead compound for CDC25 inhibition.
- Compound 6 exhibits significant anti-tumor activity in vitro and in vivo, including in patient-derived organoids.
- Further investigation of compound 6 is warranted for its potential as a therapeutic agent for lung adenocarcinoma.
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