Identification and characterisation of small molecule inhibitors of PRMT5

© 2010 Dr. Yuen Tien TanReactivation of fetal (γ−) globin gene expression is an attractive therapeutic option for various β-globin hemoglobinopathies. Symmetric methylation of H4R3 catalysed by the PRMT5 enzyme has been implicated in repressing γ−globin gene expression. Based on this, we have pursued a small molecule inhibitor of PRMT5 for reactivation of γ−globin. A radiometric assay was developed and miniaturized to screen a 100,000 chemical compound library. A second screen employing analogues of the methyl donor, S-adenosyl- methionine (SAM) was also performed. Active compounds were then analysed to determine their potential to upregulate expression of γ−globin in human erythroid progenitor cells. The work performed establishes the platform for the development of novel therapeutics for the treatment of the various β-hemoglobinopathies