2. Academic Validation
  3. Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC

Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC

  • ACS Chem Biol. 2022 Jul 15;17(7):1789-1798. doi: 10.1021/acschembio.2c00145.
Jake C Swartzel 1,  Michael J Bond 2,  Andreas P Pintado-Urbanc 1 3,  Mehana Daftary 4,  Mackenzie W Krone 5,  Todd Douglas 5,  Evan J Carder 5,  Joshua T Zimmer 3 4,  Takahiro Maeda 6,  Matthew D Simon 3 4,  Craig M Crews 1 2 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States.
  • 2 Department of Pharmacology, Yale University, New Haven, Connecticut 06511, United States.
  • 3 Institute for Biomolecular Design and Discovery, Yale University, West Haven, Connecticut 06516, United States.
  • 4 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, United States.
  • 5 Department of Molecular, Cellular, and Developmental Biology, Yale University, 260 Whitney Avenue, New Haven, Connecticut 06511, United States.
  • 6 Division of Precision Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
PMID: 35749470 DOI: 10.1021/acschembio.2c00145
Abstract

The RNA decapping scavenger protein, DcpS, has recently been identified as a dependency in acute myeloid leukemia (AML). The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by DcpS modulation. Considering this strong DcpS dependence in AML cell lines, we explored PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, a PROTAC exhibiting effective degradation of DcpS at nanomolar concentrations. JCS-1 non-covalently binds DcpS with a RG3039-based warhead and recruits the E3 Ligase VHL, which induces potent, rapid, and sustained DcpS degradation in several AML cell lines. JCS-1 serves as a chemical biology tool to interrogate DcpS degradation and associated changes in RNA processes in different cellular contexts, which may be an attractive strategy for the treatment of AML and Other DcpS-dependent genetic disorders.

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