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.

Automated summary

The RNA decapping scavenger protein DcpS has been identified as a dependency in acute myeloid leukemia (AML), and its inhibition or knockdown shows antiproliferative effects on AML cells. The non-essential nature of DcpS in normal human hematopoietic cells suggests potential for therapeutic intervention in AML by modulating DcpS activity. JCS-1, a PROTAC developed in this study, effectively degrades DcpS in nanomolar concentrations, offering a new strategy for AML and other DcpS-dependent genetic disorders.