Manumycin Polyketides Act as Molecular Glues Between UBR7 and P53
| Autor: | Scott M. Brittain, Xiaoyou Liang, Mikiko Okumura, Lynn M. McGregor, Yosuke Isobe, Daniel K. Nomura, Thomas J. Maimone, Ross White, Markus Schirle, William C. Forrester, John A. Tallarico, Michael D. Jones, Jeffrey Mckenna |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
natural products
Molecular Conformation chemistry.chemical_compound molecular glues Drug Discovery 0303 health sciences Tumor biology Molecular Structure Chemistry 030302 biochemistry & molecular biology Limiting Small molecule Ubiquitin ligase Gene Expression Regulation Neoplastic Cross-Linking Reagents Gene Knockdown Techniques Female Biochemistry & Molecular Biology Polyunsaturated Alkamides Ubiquitin-Protein Ligases Static Electricity Breast Neoplasms Antineoplastic Agents covalent ligands Computational biology Polyenes manumycin Article Cell Line 03 medical and health sciences Structure-Activity Relationship Medicinal and Biomolecular Chemistry E3 ligases Cell Line Tumor Humans Chemoproteomics asukamycin Molecular Biology protein-protein interaction (PPI) undruggable 030304 developmental biology activity-based protein profiling Neoplastic Natural product Cell Biology Anticancer mechanism chemoproteomics Gene Expression Regulation Polyketides biology.protein Breast cancer cells Biochemistry and Cell Biology Tumor Suppressor Protein p53 |
| Zdroj: | Nature chemical biology Nature chemical biology, vol 16, iss 11 |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | Molecular glues are an intriguing therapeutic modality that harness small-molecules to induce interactions between proteins that typically do not interact. However, such molecules are rare and have been discovered fortuitously, thus limiting their potential as a general strategy for therapeutic intervention. We postulated that natural products bearing one or more electrophilic sites may be an unexplored source of new molecular glues, potentially acting through multi-covalent attachment. Using chemoproteomic platforms, we show that members of the manumycin family of polyketides, which bear multiple potentially reactive sites, target C374 of the putative E3 ligase UBR7 in breast cancer cells and engage in molecular glue interactions with the neo-substrate tumor-suppressor TP53, leading to p53 transcriptional activation and cell death. Our results reveal a novel anti-cancer mechanism of this natural product family and highlight the potential for combining chemoproteomics and multi-covalent natural products for the discovery of new molecular glues. |
| Databáze: | OpenAIRE |
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