{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Mori Y"],"funding":["MEXT | Japan Society for the Promotion of Science","MEXT | Japan Society for the Promotion of Science (JSPS)","Japan Agency for Medical Research and Development","Japan Agency for Medical Research and Development (AMED)"],"pagination":["5379"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11220168"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["15(1)"],"pubmed_abstract":["Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2<sup>VHL</sup>- or CRL4<sup>CRBN</sup> -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and fo"],"journal":["Nature communications"],"pubmed_title":["Intrinsic signaling pathways modulate targeted protein degradation."],"pmcid":["PMC11220168"],"funding_grant_id":["JP20K21408","21458950","JP18H05498","JP21H02433"],"pubmed_authors":["Iio H","Saeki Y","Ushijima T","Mori Y","Tsuchimoto A","Ohtake F","Akizuki Y","Kaiho-Soma A","Honda R","Hashimoto S","Kato M","Hamazaki J","Takao M","Hattori N","Murata S"],"additional_accession":[]},"is_claimable":false,"name":"Intrinsic signaling pathways modulate targeted protein degradation.","description":"Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2<sup>VHL</sup>- or CRL4<sup>CRBN</sup> -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and fo","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jul","modification":"2026-07-15T10:30:23.782Z","creation":"2025-04-04T12:54:50.769Z"},"accession":"S-EPMC11220168","cross_references":{"pubmed":["38956052"],"doi":["10.1038/s41467-024-49519-z"]}}