Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery of 180055 as a PROTAC degrader for Treating Cancers

ABSTRACT: PARP1 is an abundant nuclear protein that is involved in a number of biological processes linked to cellular stress responses. PARP1 inhibitors (PARPi) are known to kill tumor cells via two mechanisms (PARP1 catalytic inhibition and PARP1 trapping). In this work we discovered a PROTAC degrader of PARP1 -180055, which uncoupled PARP1 trapping and inhibition. Moreover, 180055 has great potential for treating cancers.

ORGANISM(S): Homo Sapiens

SUBMITTER: Gaofeng Fan

PROVIDER: PXD042311 | iProX | Thu May 18 00:00:00 BST 2023

REPOSITORIES: iProX

ACCESS DATA

Json Xml

Similar Datasets

Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation

Project description: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.

2019-08-01 | PXD014839 | Pride

Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation

2019-08-01 | PXD014838 | Pride

Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation

2019-08-01 | PXD014840 | Pride

Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation

2019-08-01 | PXD014837 | Pride

Uncoupling of PARP1 Trapping and Inhibition Using Selective PARP1 Degradation

2019-08-01 | PXD014836 | Pride

Discovery of a Highly Potent and Selective HDAC3 and HDAC8 PROTAC Dual Degrader

Project description:Discovery of a Highly Potent and Selective HDAC3 and HDAC8 PROTAC Dual Degrader

| PRJNA872026 | ENA

BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival

Project description:BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival

| PRJNA917319 | ENA

HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation

Project description:HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation

| PRJNA947763 | ENA

Selective PROTAC-mediated degradation and shRNA-driven knockdown of SMARCA2 in HCC2302 lung adenocarcinoma cells

Project description:SMARCA2 and SMARCA4 are mutually-exclusive, core catalytic subunits for the chromatin remodeling SWI/SNF complex. Mutations in SMARCA4 are common in lung adenocarcinoma and have shown synthetic lethality with loss of SMARCA2 loss of function. The purpose of this project is to answer questions related to the in vivo [mouse xenograft] efficacy of A947, a SMARCA2 degrader. The study involves in vitro versus in vivo comparisons of drug activity, in addition to genetic manipulation of the target. Model system: HCC2302 (RRID:CVCL_V636); Model origin: Lung Adenocarcinoma; Perturbation: A947 (VHL-PROTAC-based degrader)

2022-06-13 | GSE205542 | GEO

Discovery of a Highly Potent and Selective HDAC3 and HDAC8 PROTAC Dual Degrader

Project description:HDAC3 and HDAC8 are members of class I deacetylases involved in several biological mechanisms and represent a highly sought-after therapeutic target for drug development. It is historically challenging to develop selective deacetylase inhibitors due to their conserved catalytic domains. HDAC3 also has deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Recent advance in proteolysis-targeting chimeras (PROTACs) provides an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding function. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid, and selective degradation of both HDAC3 and HDAC8 without trigging pan-HDAC inhibitory effects. Unbiased quantitative proteomics experiments further confirmed its high selectivity. This dual-specific degrader specifically ablates cellular pathways attributed to HDAC3 and HDAC8 and exhibits high potency in killing cancer cells. YX968 represents a new probe for dissecting the complex biological functions of HDAC3 and HDAC8.

2023-07-18 | GSE211758 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data