A PROTAC targets splicing factor 3B1

Cell Chem Biol. 2021 Nov 18;28(11):1616-1627.e8. doi: 10.1016/j.chembiol.2021.04.018. Epub 2021 May 27.


The proteolysis-targeting chimeras (PROTACs) are a new technology to degrade target proteins. However, their clinical application is limited currently by lack of chemical binders to target proteins. For instance, it is still unknown whether splicing factor 3B subunit 1 (SF3B1) is targetable by PROTACs. We recently identified a 2-aminothiazole derivative (herein O4I2) as a promoter in the generation of human pluripotent stem cells. In this work, proteomic analysis on the biotinylated O4I2 revealed that O4I2 targeted SF3B1 and positively regulated RNA splicing. Fusing thalidomide-the ligand of the cereblon ubiquitin ligase-to O4I2 led to a new PROTAC-O4I2, which selectively degraded SF3B1 and induced cellular apoptosis in a CRBN-dependent manner. In a Drosophila intestinal tumor model, PROTAC-O4I2 increased survival by interference with the maintenance and proliferation of stem cell. Thus, our finding demonstrates that SF3B1 is PROTACable by utilizing noninhibitory chemicals, which expands the list of PROTAC target proteins.

Keywords: CRBN; PROTAC; SF3B1 inhibitor; chemically induced protein-protein interaction; molecular degrader; proteomics; proximity-based drug; splicing factor 3B1; targeted protein degradation; thalidomide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drosophila melanogaster
  • Humans
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / metabolism
  • Proteolysis / drug effects
  • RNA Splicing / drug effects
  • RNA Splicing Factors / antagonists & inhibitors*
  • RNA Splicing Factors / metabolism
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*


  • Phosphoproteins
  • RNA Splicing Factors
  • SF3B1 protein, human
  • Thiazoles
  • 2-aminothiazole