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

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.