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 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.

Concise Asymmetric Syntheses of Streptazone A and Abikoviromycin**

“…From a biological perspective, this data supports that 1 can act as a cysteine‐reactive natural product and potentially also with the ability to facilitate cross‐linking [37] . We anticipate that this highly peculiar reactivity will manifest itself in biological studies of this natural product family.…”

Discovery of a molecular glue that enhances UPRmtto restore proteostasisviaTRKA-GRB2-EVI1-CRLS1 axis

“…2H-I). The function of Rg3 is quite unique than other molecular glue that normally aim to degrade target proteins [42,43]. To our knowledge, this is the first molecular glue that activates a tyrosine kinase receptor.…”

Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation

“…42 We are also learning about novel modes of TPD, as seen with the recent publications of a covalent natural product molecular glue and a small molecule that induces BCL6 polymerization and degradation. 139,140 It is possible that these mechanisms may also become prominent areas of TPD research. However, it is likely that PROTACs, and the TPD field they inspired, will continue pushing the boundaries of drug discovery for the foreseeable future.…”