A novel quinoid-based CDC25 phosphatase inhibitor against human lung adenocarcinoma across different models

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.

Keywords: Apoptosis; CDC25 phosphatase inhibitor; Lung adenocarcinoma; Patient-derived organoid; Quinoid structure.