Discovery of a novel Aurora B inhibitor GSK650394 with potent anticancer and anti-aspergillus fumigatus dual efficacies in vitro

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 37; no. 1; pp. 109 - 117
• Main Authors: He, Yuhua, Fu, Wei, Du, Liyang, Yao, Huiqiao, Hua, Zhengkang, Li, Jinyu, Lin, Zhonghui
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.12.2022; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: anti-aspergillus fumigatus; anti-cancer; Antibodies; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Aspergillosis; Aspergillus fumigatus; Aspergillus fumigatus - drug effects; Aurora B; Aurora B protein; Aurora Kinase B - antagonists & inhibitors; Aurora Kinase B - metabolism; Benzoates - chemistry; Benzoates - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cancer; Cancer therapies; Candidiasis; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell division; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Drugs; Flow cytometry; Fungal infections; Humans; inhibitor; Invasiveness; Kinases; Microbial Sensitivity Tests; Molecular Structure; Morbidity; Protein expression; Proteins; Research Paper; Site-directed mutagenesis; Structure-Activity Relationship; Tumor Cells, Cultured; Yeast; inhibitor; Aurora B; anti-cancer; anti-aspergillus fumigatus
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2021.1975693

Invasive fungal infections including Candidiasis and Aspergillosis are associated with considerable morbidity and mortality in immunocompromised individuals, such as cancer patients. Aurora B is a key mitotic kinase required for the cell division of eukaryotes from fungus to man. Here, we identified a novel Aurora B inhibitor GSK650394 that can inhibit the recombinant Aurora B from human and Aspergillus fumigatus, with IC 50 values of 5.68 and 1.29 µM, respectively. In HeLa and HepG2 cells, GSK650394 diminishes the endogenous Aurora B activity and causes cell cycle arrest in G2/M phase. Further cell-based assays demonstrate that GSK650394 efficiently suppresses the proliferation of both cancer cells and Aspergillus fumigatus. Finally, the molecular docking calculation and site-directed mutagenesis analyses reveal the molecular mechanism of Aurora B inhibition by GSK650394. Our work is expected to provide new insight into the combinational therapy of cancer and Aspergillus fumigatus infection.