Premium
Targeted Degradation of PARP14 Using a Heterobifunctional Small Molecule
Author(s) -
Wigle Tim J.,
Ren Yue,
Molina Jennifer R.,
Blackwell Danielle J.,
Schenkel Laurie B.,
Swinger Kerren K.,
KuplastBarr Kristy,
Majer Christina R.,
Church W. David,
Lu Alvin Z.,
Mo Jason,
Abo Ryan,
Cheung Anne,
Dorsey Bryan W.,
Niepel Mario,
Perl Nicholas R.,
Vasbinder Melissa M.,
Keilhack Heike,
Kuntz Kevin W.
Publication year - 2021
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202100047
Subject(s) - small molecule , ribose , biochemistry , microbiology and biotechnology , enzyme , nad+ kinase , poly adp ribose polymerase , biology , chemistry , biophysics , polymerase
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.