Pluripotent stem cell‐based screening identifies CUDC‐907 as an effective compound for restoring the in vitro phenotype of Nakajo‐Nishimura syndrome

Nakajo‐Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in the PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)‐derived NNS disease model that reproduces several inflammatory phenotypes, including the overproduction of monocyte chemoattractant protein‐1 (MCP‐1) and interferon gamma‐induced protein‐10 (IP‐10). Here we performed high‐throughput compound screening (HTS) using this PSC‐derived NNS model to find potential therapeutic candidates and identified CUDC‐907 as an effective inhibitor of the release of MCP‐1 and IP‐10. Short‐term treatment of CUDC‐907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post‐transcriptional. These findings suggest that HTS with PSC‐derived disease models is useful for finding drug candidates for autoinflammatory diseases. High‐throughput screening using pluripotent stem cell‐derived monocytic cell lines was performed to identify potential therapeutic candidates of Nakajo‐Nishimura syndrome. The hit compound, CUDC‐907 effectively inhibits the overproduction of inflammatory chemokines, monocyte chemoattractant protein‐1, and interferon gamma‐induced protein‐10.