CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma

Nat Chem Biol. 2020 Jan;16(1):50-59. doi: 10.1038/s41589-019-0424-1. Epub 2019 Dec 9.


The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Binding Sites
  • Carboxylic Ester Hydrolases / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Cleavage And Polyadenylation Specificity Factor / genetics
  • Cleavage And Polyadenylation Specificity Factor / metabolism*
  • HEK293 Cells
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / metabolism*
  • Male
  • Mass Spectrometry
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Phenotype
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / pharmacology
  • Piperazines / pharmacology
  • Protein Binding
  • RNA Precursors / metabolism*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Sarcoma, Ewing / drug therapy
  • Sarcoma, Ewing / metabolism*


  • CPSF3 protein, human
  • Cleavage And Polyadenylation Specificity Factor
  • JTE 607
  • Piperazines
  • RNA Precursors
  • RNA, Messenger
  • RNA, Small Interfering
  • Phenylalanine
  • Carboxylic Ester Hydrolases
  • CES1 protein, human