2. Academic Validation
  3. Remodeling oncogenic transcriptomes by small molecules targeting NONO

Remodeling oncogenic transcriptomes by small molecules targeting NONO

  • Nat Chem Biol. 2023 Jul;19(7):825-836. doi: 10.1038/s41589-023-01270-0.
Stefan G Kathman # 1,  Seong Joo Koo # 2,  Garrett L Lindsey # 3,  Hsuan-Lin Her 4,  Steven M Blue 5,  Haoxin Li 3,  Steffen Jaensch 6,  Jarrett R Remsberg 3,  Kay Ahn 7,  Gene W Yeo 8,  Brahma Ghosh 9,  Benjamin F Cravatt 10
Affiliations

Affiliations

  • 1 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. [email protected].
  • 2 Molecular and Cellular Pharmacology, Discovery Technologies and Molecular Pharmacology, Janssen Research and Development, Beerse, Belgium.
  • 3 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • 4 Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA, USA.
  • 5 Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • 6 High Dimensional and Computational Biology, Discovery Technologies and Molecular Pharmacology, Janssen Research and Development, Beerse, Belgium.
  • 7 Molecular and Cellular Pharmacology, Discovery Technologies and Molecular Pharmacology, Janssen Research and Development, Spring House, PA, USA. [email protected].
  • 8 Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA. [email protected].
  • 9 Discovery Chemistry, Janssen Research and Development, Spring House, PA, USA. [email protected].
  • 10 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. [email protected].
  • # Contributed equally.
PMID: 36864190 DOI: 10.1038/s41589-023-01270-0
Abstract

Much of the human proteome is involved in mRNA homeostasis, but most RNA-binding proteins lack chemical probes. Here we identify electrophilic small molecules that rapidly and stereoselectively decrease the expression of transcripts encoding the Androgen Receptor and its splice variants in prostate Cancer cells. We show by chemical proteomics that the compounds engage C145 of the RNA-binding protein NONO. Broader profiling revealed that covalent NONO ligands suppress an array of cancer-relevant genes and impair Cancer cell proliferation. Surprisingly, these effects were not observed in cells genetically disrupted for NONO, which were instead resistant to NONO ligands. Reintroduction of wild-type NONO, but not a C145S mutant, restored ligand sensitivity in NONO-disrupted cells. The ligands promoted NONO accumulation in nuclear foci and stabilized NONO-RNA interactions, supporting a trapping mechanism that may prevent compensatory action of paralog proteins PSPC1 and SFPQ. These findings show that NONO can be co-opted by covalent small molecules to suppress protumorigenic transcriptional networks.

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