In Vitro and Cellular Probes to Study PARP Enzyme Target Engagement

Wigle, Tim J.; Blackwell, Danielle J.; Schenkel, Laurie B.; Ren, Yue; Church, W. David; Desai, Hetvi J.; Swinger, Kerren K.; Santospago, Andrew G.; Majer, Christina R.; Lu, Alvin Z.; Niepel, Mario; Perl, Nicholas R.; Vasbinder, Melissa M.; Keilhack, Heike; Kuntz, Kevin W.

doi:10.1016/j.chembiol.2020.06.009

Cited by 21 publications

(16 citation statements)

References 42 publications

(56 reference statements)

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“…RBN012811 was designed based upon a potent and selective PARP14 catalytic inhibitor, RBN012042 (Figure 2 and Table S1; PDB ID: 7 L9Y). We exploited a solvent‐exposed vector to add a linker and thalidomide moiety, and the resulting compound maintained its selectivity and potency for PARP14 based upon biochemical and biophysical assays [20–21] . We measured metabolic stability of the compounds in mouse liver microsomes, and while RBN012042 had low turnover, RBN012811 had high turnover (Table S2).…”

Section: Figurementioning

confidence: 99%

Targeted Degradation of PARP14 Using a Heterobifunctional Small Molecule

et al. 2021

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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.

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Section: Figurementioning

confidence: 99%

Targeted Degradation of PARP14 Using a Heterobifunctional Small Molecule

et al. 2021

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“…In the first years, the developed inhibitors were designed targeting a group of ART enzymes; in recent years, novel compounds have been developed specifically for a single ART enzyme, with effects in the nanomolar concentration. For instance, there are new inhibitors targeting just ARTD10 [ 126 , 130 , 131 , 132 , 133 ], ARTD11 [ 128 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 ], or ARTD14/PARP7 [ 145 , 146 , 147 ].…”

Section: Cancer Proliferation Metastasis Angiogenesis: the Role Of Adp-ribosylating Enzymes According To A Deregulated Expression Or Use mentioning

confidence: 99%

ADP-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

Poltronieri

Misawa

Masutani

2021

IJMS

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Among the post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, and a large set of functions, including DNA repair, transcription, and cell signaling, have been assigned to this post-translational modification (PTM). This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing monoADP-ribosylation/polyADP-ribosylation (MAR/PAR) cycling in cancers. Of note, there is potential for the application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, the suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

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“…In the beginning years, the developed inhibitors were designed targeting a group of ART enzymes; in recent years, novel compounds have been developed specific for a single ART enzyme, with effects at nanomolar concentration. For instance, there are new inhibitors targeting just ARTD10 [120,[127][128][129][130], ARTD11 [122,[131][132][133][134][135][136][137][138][139][140][141][142][143][144]. or ARTD14/PARP7 [142][143][144].…”

Section: Other Marylating Art Enzymes Linked To Cancer and Potential Enzyme Inhibitorsmentioning

confidence: 99%

“…ARTD14/PARP7 is amplified and highly expressed in squamous cell carcinomas, in ovarian and lung tumors, and is associated with poor survival [135][136][137]. Protein substrates MARylation, such as α-tubulin, by ARTD14/PARP7, has a role in microtubule control in ovarian cancer [138,143,144].…”

Section: Other Marylating Art Enzymes Linked To Cancer and Potential Enzyme Inhibitorsmentioning

confidence: 99%

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

Poltronieri¹,

Misawa²,

Masutani³

2021

Preprint

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Among post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, assigning to this PTM a large set of functions, including DNA repair, transcription and cell signaling. This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing MAR/PAR cycling in cancers. Of note, there is potential for application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

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In Vitro and Cellular Probes to Study PARP Enzyme Target Engagement

Cited by 21 publications

References 42 publications

Targeted Degradation of PARP14 Using a Heterobifunctional Small Molecule

Targeted Degradation of PARP14 Using a Heterobifunctional Small Molecule

ADP-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

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