Drug repurposing screen identifies novel anti-inflammatory activity of sunitinib in macrophages

Abstract

Inflammation is a driver of human disease and an unmet clinical need exists for new anti-inflammatory medicines. As a key cell type in both acute and chronic inflammatory pathologies, macrophages are an appealing therapeutic target for anti-inflammatory medicines. Drug repurposing - the use of existing medicines for novel indications - is an attractive strategy for the identification of new anti-inflammatory medicines with reduced development costs and lower failure rates than de novo drug discovery. In this study, FDA-approved medicines were screened in a murine macrophage NF-κB reporter cell line to identify potential anti-inflammatory drug repurposing candidates. The multi-tyrosine kinase inhibitor sunitinib was found to be a potent inhibitor of NF-κB activity and suppressor of inflammatory mediator production in murine bone marrow derived macrophages. Furthermore, oral treatment with sunitinib in mice was found to reduce TNFα production, inflammatory gene expression and organ damage in a model of endotoxemia via inhibition of NF-κB. Finally, we revealed sunitinib to have immunomodulatory effects in a model of chronic cardiovascular inflammation by reducing circulating TNFα. This study validates drug repurposing as a strategy for the identification of novel anti-inflammatory medicines and highlights sunitinib as a potential drug repurposing candidate for inflammatory disease via inhibition of NF-κB signalling.

Keywords: Atherosclerosis; Drug repurposing; Inflammation; Macrophage; NF-κB.