Precise Conformational Control Yielding Highly Potent and Exceptionally Selective BRD4 Degraders with Strong Antitumor Activity
dc.contributor.author | Hu, J | |
dc.contributor.author | Hu, B | |
dc.contributor.author | Xu, F | |
dc.contributor.author | Wang, M | |
dc.contributor.author | Qin, C | |
dc.contributor.author | McEachern, D | |
dc.contributor.author | Stuckey, J | |
dc.contributor.author | Wang, S | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2024-03-21T17:49:10Z | |
dc.date.available | 2024-03-21T17:49:10Z | |
dc.date.issued | 2023-06-22 | |
dc.identifier.issn | 0022-2623 | |
dc.identifier.issn | 1520-4804 | |
dc.identifier.uri | https://www.ncbi.nlm.nih.gov/pubmed/37289649 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/192651 | en |
dc.description.abstract | Starting from a nonselective bromodomain and extraterminal (BET) inhibitor and a cereblon ligand, we have used precise conformational control for the development of two potent and highly selective BRD4 degraders, BD-7148 and BD-9136. These compounds induce rapid degradation of BRD4 protein in cells at concentrations as low as 1 nM and demonstrate ≥1000-fold degradation selectivity over BRD2 or BRD3 protein. Proteomic analysis of >5700 proteins confirmed their highly selective BRD4 degradation. A single dose of BD-9136 selectively and effectively depletes BRD4 protein in tumor tissues for >48 h. BD-9136 effectively inhibits tumor growth without adverse effects on mice and is more efficacious than the corresponding pan BET inhibitor. This study suggests selective degradation of BRD4 as a strategy for the treatment of human cancers and demonstrates a strategy for the design of highly selective PROTAC degraders. | |
dc.format.medium | Print-Electronic | |
dc.language | eng | |
dc.publisher | American Chemical Society (ACS) | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Animals | |
dc.subject | Nuclear Proteins | |
dc.subject | Cell Cycle Proteins | |
dc.subject | Transcription Factors | |
dc.subject | Proteomics | |
dc.subject | Neoplasms | |
dc.title | Precise Conformational Control Yielding Highly Potent and Exceptionally Selective BRD4 Degraders with Strong Antitumor Activity | |
dc.type | Article | |
dc.identifier.pmid | 37289649 | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/192651/2/Precise Conformational Control Yielding Highly Potent and Exceptionally Selective BRD4 Degraders with Strong Antitumor Activity.pdf | |
dc.identifier.doi | 10.1021/acs.jmedchem.3c00520 | |
dc.identifier.doi | https://dx.doi.org/10.7302/22467 | |
dc.identifier.source | Journal of Medicinal Chemistry | |
dc.description.version | Published version | |
dc.date.updated | 2024-03-21T17:49:05Z | |
dc.identifier.orcid | 0009-0007-4782-8779 | |
dc.identifier.orcid | 0000-0002-4691-6490 | |
dc.identifier.orcid | 0000-0002-5908-4072 | |
dc.identifier.orcid | 0000-0001-8108-1698 | |
dc.identifier.orcid | 0000-0002-4192-8900 | |
dc.identifier.orcid | 0000-0002-8782-6950 | |
dc.description.filedescription | Description of Precise Conformational Control Yielding Highly Potent and Exceptionally Selective BRD4 Degraders with Strong Antitumor Activity.pdf : Published version | |
dc.identifier.volume | 66 | |
dc.identifier.issue | 12 | |
dc.identifier.startpage | 8222 | |
dc.identifier.endpage | 8237 | |
dc.identifier.name-orcid | Hu, J; 0009-0007-4782-8779 | |
dc.identifier.name-orcid | Hu, B; 0000-0002-4691-6490 | |
dc.identifier.name-orcid | Xu, F | |
dc.identifier.name-orcid | Wang, M; 0000-0002-5908-4072 | |
dc.identifier.name-orcid | Qin, C; 0000-0001-8108-1698 | |
dc.identifier.name-orcid | McEachern, D | |
dc.identifier.name-orcid | Stuckey, J; 0000-0002-4192-8900 | |
dc.identifier.name-orcid | Wang, S; 0000-0002-8782-6950 | |
dc.working.doi | 10.7302/22467 | en |
dc.owningcollname | Internal Medicine, Department of |
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