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

Jake C Swartzel1, Michael J Bond2, Andreas P Pintado-Urbanc1,3

  • 1Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States.

ACS Chemical Biology
|June 24, 2022
PubMed

Insights

Researchers developed JCS-1, a novel PROTAC, to degrade DcpS (decapping scavenger protein) in acute myeloid leukemia (AML) cells. This targeted degradation offers a promising therapeutic strategy for AML, as DcpS is non-essential in healthy cells.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • The RNA decapping scavenger protein, DcpS, is a newly identified dependency in acute myeloid leukemia (AML).
  • DcpS inhibition or knockdown shows antiproliferative effects in AML cells.
  • DcpS is non-essential in normal hematopoietic cells, suggesting a therapeutic window for AML treatment.

Purpose of the Study:

  • To explore Proteolysis-Targeting Chimeras (PROTACs) for DcpS modulation in AML.
  • To develop a PROTAC-mediated strategy for targeted DcpS degradation.

Main Methods:

  • Development and characterization of JCS-1, a novel PROTAC molecule.
  • Assessment of JCS-1's efficacy in degrading DcpS in AML cell lines.
  • Utilizing a RG3039-based warhead and VHL E3 ligase recruitment.

Main Results:

  • JCS-1 effectively degrades DcpS at nanomolar concentrations.
  • JCS-1 induces potent, rapid, and sustained DcpS degradation in multiple AML cell lines.
  • The PROTAC JCS-1 demonstrates non-covalent binding to DcpS.

Conclusions:

  • PROTAC-mediated degradation is a viable strategy for targeting DcpS in AML.
  • JCS-1 serves as a valuable chemical biology tool for studying DcpS degradation and RNA processes.
  • Targeting DcpS degradation presents an attractive therapeutic approach for AML and other DcpS-dependent disorders.

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