Targeted Degradation of PARP14 Using a Heterobifunctional Small Molecule.

Chembiochem : a European journal of chemical biology 2021 Jun 15

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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-γ 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. © 2021 Wiley-VCH GmbH.

Citation

Tim J Wigle, Yue Ren, Jennifer R Molina, Danielle J Blackwell, Laurie B Schenkel, Kerren K Swinger, Kristy Kuplast-Barr, Christina R Majer, W David Church, Alvin Z Lu, Jason Mo, Ryan Abo, Anne Cheung, Bryan W Dorsey, Mario Niepel, Nicholas R Perl, Melissa M Vasbinder, Heike Keilhack, Kevin W Kuntz. Targeted Degradation of PARP14 Using a Heterobifunctional Small Molecule. Chembiochem : a European journal of chemical biology. 2021 Jun 15;22(12):2107-2110