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.

分子胶是一种有趣的治疗方法，利用小分子来诱导通常不相互作用的蛋白质之间的相互作用。然而，这种分子是罕见的并且是偶然发现的，因此限制了它们作为治疗干预的一般策略的潜力。我们推测带有一个或多个亲电位点的天然产物可能是新分子胶的未开发来源，可能通过多价共价键作用。使用化学旋转平台，我们显示了manumycin家族的聚酮化合物成员具有多个潜在的反应位点，靶向乳腺癌细胞中假定的E3连接酶UBR7的C374，并与新底物肿瘤抑制剂TP53进行分子胶相互作用，从而导致p53转录激活和细胞死亡。