2. Academic Validation
  3. Targeted Degradation of PARP14 Using a Heterobifunctional Small Molecule

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

Affiliation

  • 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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