Targeted Degradation of PARP14 Using a Heterobifunctional Small Molecule

  • Chembiochem. 2021 Jun 15;22(12):2107-2110. doi: 10.1002/cbic.202100047.
Tim J Wigle  1 ,  Yue Ren  1 ,  Jennifer R Molina  1 ,  Danielle J Blackwell  1 ,  Laurie B Schenkel  1 ,  Kerren K Swinger  1 ,  Kristy Kuplast-Barr  1 ,  Christina R Majer  1 ,  W David Church  1 ,  Alvin Z Lu  1 ,  Jason Mo  1 ,  Ryan Abo  1 ,  Anne Cheung  1 ,  Bryan W Dorsey  1 ,  Mario Niepel  1 ,  Nicholas R Perl  1 ,  Melissa M Vasbinder  1 ,  Heike Keilhack  1 ,  Kevin W Kuntz  1
Affiliations
  • 1. Ribon Therapeutics, 35 Cambridgepark Dr., Suite 300, Cambridge, MA 02140, USA.
PMID: 33838082 DOI: 10.1002/cbic.202100047
Abstract

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.

Keywords
ADP-ribosylation; IL-4; PARP14; degrade; macrophages.
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