Manumycin polyketides act as molecular glues between UBR7 and P53.

Abstract

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 multicovalent 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 neosubstrate tumor-suppressor TP53, leading to p53 transcriptional activation and cell death. Our results reveal an anticancer mechanism of this natural product family, and highlight the potential for combining chemoproteomics and multicovalent natural products for the discovery of new molecular glues.

• Authors: Yosuke Isobe, Mikiko Okumura, Lynn M McGregor, Scott M Brittain, Michael D Jones, Xiaoyou Liang, Ross White, William Forrester, Jeffrey M McKenna, John A Tallarico, Markus Schirle, Thomas J Maimone, Daniel K Nomura
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 16 Issue 11 Pg. 1189-1198 (11 2020) ISSN: 1552-4469 [Electronic] United States
• PMID: 32572277 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cross-Linking Reagents
• Polyenes
• Polyketides
• Polyunsaturated Alkamides
• TP53 protein, human
• Tumor Suppressor Protein p53
• UBR7 protein, human
• asukamycin
• Ubiquitin-Protein Ligases
• manumycin

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Cross-Linking Reagents (chemistry)
• Drug Discovery
• Female
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Molecular Conformation
• Molecular Structure
• Polyenes (chemistry, pharmacology)
• Polyketides (chemistry)
• Polyunsaturated Alkamides (chemistry, pharmacology)
• Static Electricity
• Structure-Activity Relationship
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)