New target to combat AML and Ewing’s sarcoma

JTE-607, a cell-permeable prodrug which is converted to its active COOH form via intracellular esterases, was originally found to inhibit cytokine release but its mechanism of action was unknown. More recently it was shown to inhibit pre-mRNA processing via inhibition of the endonuclease Cleavage and Polyadenylation Specificity Factor 3 (CPSF3), preventing the release of newly synthesized pre-mRNAs, which results in read-through transcription and the formation of DNA-RNA hybrid R-loops. Using JTE-607 as a tool compound, CPSF3 was shown to be a druggable target for AML and Ewing’s sarcoma.