Proteomics

Dataset Information

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Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation


ABSTRACT: PARP1 inhibitors (PARPi) are known to kill tumor cells via two mechanisms (i.e., PARP1 catalytic inhibition vs. PARP1 trapping). The relative contribution of these two pathways in mediating the cytotoxicity of PARPi, however, is incompletely understood. Here we designed a series of small molecule PARP degraders. Treatment with one such compound iRucaparib (1) results in highly efficient and specific PARP1 degradation. iRucaparib blocks the enzymatic activity of PARP1 in vitro, and PARP1-mediated PARylation signaling in intact cells. This strategy mimics PARP1 genetic depletion, which enables the pharmacological decoupling of PARP1 inhibition from PARP1 trapping. Finally, by depleting PARP1, iRucaparib protects muscle cells and primary cardiomyocytes from DNA damage-induced energy crisis and cell death. In summary, these compounds represent “non-trapping” PARP1 degraders that block both the catalytic activity and scaffolding effects of PARP1, providing an ideal approach for the amelioration of the various pathological conditions caused by PARP1 hyperactivation.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Cervix Carcinoma

SUBMITTER: Shuai Wang  

LAB HEAD: Yonghao Yu

PROVIDER: PXD014840 | Pride | 2019-08-01

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
F10376.raw Raw
F10376_Rucap.pep.xml Pepxml
F10376_Rucap.xlsx Xlsx
F10379.raw Raw
F10379_iRucap-TP3.pep.xml Pepxml
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Publications

Uncoupling of PARP1 trapping and inhibition using selective PARP1 degradation.

Wang Shuai S   Han Lei L   Han Jungsoo J   Li Peng P   Ding Qing Q   Zhang Qing-Jun QJ   Liu Zhi-Ping ZP   Chen Chuo C   Yu Yonghao Y  

Nature chemical biology 20191028 12


PARP1 inhibitors (PARPi) are known to kill tumor cells via two mechanisms (PARP1 catalytic inhibition and PARP1 trapping). The relative contribution of these two pathways in mediating the cytotoxicity of PARPi, however, is not well understood. Here we designed a series of small molecule PARP degraders. Treatment with one such compound iRucaparib-AP6 results in highly efficient and specific PARP1 degradation. iRucaparib-AP6 blocks the enzymatic activity of PARP1 in vitro, and PARP1-mediated poly-  ...[more]

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