Manumycin polyketides act as molecular glues between UBR7 and P53

• Published in: Nature chemical biology Vol. 16; no. 11; pp. 1189 - 1198
• Main Authors: Isobe, Yosuke, Okumura, Mikiko, McGregor, Lynn M., Brittain, Scott M., Jones, Michael D., Liang, Xiaoyou, White, Ross, Forrester, William, McKenna, Jeffrey M., Tallarico, John A., Schirle, Markus, Maimone, Thomas J., Nomura, Daniel K.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2020; Nature Publishing Group
• Subjects: 631/67; 631/92/349; 631/92/475; 631/92/555; Adhesives; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Breast cancer; Breast Neoplasms - drug therapy; Cell activation; Cell Biology; Cell death; Cell Line, Tumor; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Cross-Linking Reagents - chemistry; Drug Discovery; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glues; Humans; Molecular Conformation; Molecular Structure; Natural products; p53 Protein; Polyenes - chemistry; Polyenes - pharmacology; Polyketides; Polyketides - chemistry; Polyunsaturated Alkamides - chemistry; Polyunsaturated Alkamides - pharmacology; Static Electricity; Structure-Activity Relationship; Transcription activation; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-020-0557-2

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. Manumycin natural products were found to target the E3 ligase UBR7 and engage in molecular glue interactions with p53, leading to the activation of p53 and cell death.