We identified small molecules that rewire the transcriptional state of cancer cells by covalently targeting the RNA-binding protein NONO. These small molecules stabilize the interactions of NONO with its target mRNAs, thereby overriding the compensatory action of paralog proteins and revealing a pharmacological strategy for disrupting previously undruggable oncogenic pathways.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Snow, O. et al. Androgen receptor plasticity and its implication for prostate cancer therapy. Cancer Treat. Rev. 81, 101871 (2019). A review article describing mechanisms of resistance to androgen receptor antagonists.
Wu, P. Inhibition of RNA-binding proteins with small molecules. Nat. Rev. Chem. 4, 441–458 (2020). A review article that presents opportunities and challenges in targeting RNA-biding proteins with small molecules.
Backus, K. M. et al. Proteome-wide covalent ligand discovery in native biological systems. Nature 534, 570–574 (2016). This paper describes how integrating covalent chemistry and chemical proteomics can enable the discovery of ligands for many proteins.
Li, S. et al. Double-strand break repair deficiency in NONO knockout murine embryonic fibroblasts and compensation by spontaneous upregulation of the PSPC1 paralog. Nucleic Acids Res. 42, 9771–9780 (2014). This paper describes how genetic loss of NONO is compensated for by paralog proteins.
Vinogradova, E. V. et al. An activity-guided map of electrophile-cysteine interactions in primary human T cells. Cell 182, 1009–1026 (2020). This paper describes electrophilic compound designs that leverage stereochemistry to map small molecule–cysteine interactions by chemical proteomics.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This is a summary of: Kathman, S. G. et al. Remodeling oncogenic transcriptomes by small molecules targeting NONO. Nat. Chem. Bio. https://doi.org/10.1038/s41589-023-01270-0 (2023).
Rights and permissions
About this article
Cite this article
Small-molecule trapping of an RNA-binding protein blocks cancer cell growth. Nat Chem Biol 19, 803–804 (2023). https://doi.org/10.1038/s41589-023-01271-z
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41589-023-01271-z
