2. Academic Validation
  3. A PROTAC targets splicing factor 3B1

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.
Rodrigo A Gama-Brambila 1,  Jie Chen 1,  Jun Zhou 2,  Georg Tascher 3,  Christian Münch 3,  Xinlai Cheng 4
Affiliations

Affiliations

  • 1 Buchmann Institute for Molecular Life Sciences, Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue-Strasse 15. R. 3.652, 60438 Frankfurt am Main, Germany.
  • 2 Division Signaling and Functional Genomics, Department for Cell and Molecular Biology, Medical Faculty Mannheim, German Cancer Research Center and Heidelberg University, 69120 Heidelberg, Germany.
  • 3 Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt am Main, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
  • 4 Buchmann Institute for Molecular Life Sciences, Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue-Strasse 15. R. 3.652, 60438 Frankfurt am Main, Germany. Electronic address: cheng@pharmchem.uni-frankfurt.de.
PMID: 34048672 DOI: 10.1016/j.chembiol.2021.04.018
Abstract

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.

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