Development of in vitro safety screening strategy for RNA-targeted small molecules

抄録

“New modality” is an emerging area in drug discovery to open new therapeutic fields that were challenging for conventional small molecules. As well as other new modalities such as oligonucleotide or AAV-based gene therapy, a increasing number of non-conventional small molecules were reported with novel mechanism of actions such as RNA modulation or protein degradation. Among them, RNA splicing modulator is one of key fields where a frontrunner compound, Risdiplam, was approved by FDA in 2020. Though published data is still limited for RNA splicing modulators, it would not be surprising that chemical space of RNA modulator is different from one of conventional small molecule due to different chemical properties of RNAs from proteins. Therefore, early de-risking strategy should be updated especially for RNA-targeted small molecules. In this talk, I would like to share chemical properties analysis of known RNA-targeted small molecules and potential in vitro safety screening strategy including assessment for chemical space related safety risks such as hERG inhibition and phototoxicity.