Abstract

[Introduction] Recently, drug repositioning is becoming a popular as a new approach to develop a novel therapeutic reagent.

[Aims and objectives] The aim of this study was to identify novel therapeutic options for idiopathic pulmonary fibrosis (IPF) using a systematic computational approach for drug repositioning.

[Method] Microarray data of IPF patients were extracted from the Gene Expression Omnibus database and analyzed for gene expression. We used the L1000 Characteristic Direction Signature Search Engine, a drug discovery tool provided by the NIH to search for approved drugs that counteract gene expression of IPF. The experimental lung fibrosis was induced in mice by bronchial administration of bleomycin. Mice received intraperitoneal instillation of candidates twice a week. The fibrotic changes in the lungs were assessed on day 21.

[Results] Computational drug repositioning predicted that BI2536, a polo-like kinase (PLK) 1/2 inhibitor as a new therapeutic agent for IPF. However, BI2536 accelerated mortality and weight loss in experimental pulmonary fibrosis model in mice. Because the immunofluorescence staining revealed that PLK1 expression was dominant in myofibroblasts, while PLK2 expression was dominant in lung epithelial cells, we next focused on GSK461364, selective PLK1 inhibitor. As a results, GSK461364 attenuated pulmonary fibrosis with acceptable mortality and weight loss in mice.

[Conclusion] Targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis. In addition, while in silico screening is useful, it is essential to determine the biological activities of candidates by wet-lab validation studies.