Journal
CHEMBIOCHEM
Volume 22, Issue 12, Pages 2107-2110Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202100047
Keywords
ADP-ribosylation; degrade; IL-4; macrophages; PARP14
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The overexpression of PARP14 in multiple tumor types influences macrophage polarization and anti-tumor inflammation response. PARP14 is a protein with a catalytic domain and non-enzymatic biomolecular recognition motifs. A newly developed heterobifunctional small molecule selectively targets PARP14 for degradation.
PARP14 is an interferon-stimulated gene that is overexpressed in multiple tumor types, influencing pro-tumor macrophage polarization as well as suppressing the antitumor inflammation response by modulating IFN-gamma and IL-4 signaling. PARP14 is a 203 kDa protein that possesses a catalytic domain responsible for the transfer of mono-ADP-ribose to its substrates. PARP14 also contains three macrodomains and a WWE domain which are binding modules for mono-ADP-ribose and poly-ADP-ribose, respectively, in addition to two RNA recognition motifs. Catalytic inhibitors of PARP14 have been shown to reverse IL-4 driven pro-tumor gene expression in macrophages, however it is not clear what roles the non-enzymatic biomolecular recognition motifs play in PARP14-driven immunology and inflammation. To further understand this, we have discovered a heterobifunctional small molecule designed based on a catalytic inhibitor of PARP14 that binds in the enzyme's NAD(+)-binding site and recruits cereblon to ubiquitinate it and selectively target it for degradation.
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