JTE-607, a multiple cytokine production inhibitor, targets CPSF3 and inhibits pre-mRNA processing

Abstract

JTE-607 is a small molecule that was developed as an inflammatory cytokine inhibitor and also as an anti-leukemia reagent for monocytic leukemia. However, the mode of action of JTE-607 remains unknown. In this study, we identified JTE-607 to be a prodrug compound that is converted to an active form by ester hydrolysis. Furthermore, we determined that the active form of JTE-607 bound cleavage and polyadenylation specificity factor subunit 3 (CPSF3), using compound-immobilized affinity chromatography. CPSF3 is a 73-kDa subunit of the cleavage and polyadenylation specificity factor complex, which functions as an RNA endonuclease. The protein is involved in the 3'-end processing of messenger RNA precursors (pre-mRNAs) at the cleavage site located downstream of the poly(A) addition signal. We found that treatment with JTE-607 caused accumulation of pre-mRNAs. Furthermore, knockdown experiments showed that CPSF3 deficiency also caused accumulation of pre-mRNAs and suppressed the expression of inflammatory cytokines, like JTE-607. These findings indicated that CPSF3 is a direct target of JTE-607 and a new potential target for the treatment of disease-related abnormal cytokine production.

Keywords: CPSF3; Compound-immobilized affinity chromatography; Cytokine; JTE-607; Prodrug; mRNA 3′-end processing.