Evidence map›Paper›PMID 41534524›Full record

ArticleCell chemical biology2026

Structural and mechanistic analysis of covalent ligands targeting the RNA-binding protein NONO.

Garrett L Lindsey, Thomas K Hockley, Alejandro Villa Gomez, Andrew C Marshall, William R Brothers, Colin T Finney, Jacob Gross, Archa H Fox, Gene W Yeo, Bruno Melillo and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell chemical biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Engineering a protein homodimer from a heterodimer: A chimeric DBHS protein.Protein science : a publication of the Protein Society · 2026
    Article
  2. Review
  3. Article
  4. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors.

Garrett L LindseyDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Thomas K HockleySchool of Molecular Sciences, The University of Western Australia, Crawley, WA 6009, Australia.
Alejandro Villa GomezSchool of Molecular Sciences, The University of Western Australia, Crawley, WA 6009, Australia.
Andrew C MarshallSchool of Molecular Sciences, The University of Western Australia, Crawley, WA 6009, Australia.
William R BrothersDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Colin T FinneyDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Jacob GrossVividion Therapeutics, 5820 Nancy Ridge Drive, San Diego, CA 92121, USA.
Archa H FoxSchool of Human Sciences, The University of Western Australia, Crawley, WA 6009, Australia.
Gene W YeoDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Bruno MelilloDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Charles S BondSchool of Molecular Sciences, The University of Western Australia, Crawley, WA 6009, Australia. Electronic address: charles.bond@uwa.edu.au.
Benjamin F CravattDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: cravatt@scripps.edu.

Funding

Chemical Proteomic Platforms for Radically Expanding Cancer DruggabilityR35CA231991 · NCI · SCRIPPS RESEARCH INSTITUTE, THE · PI BENJAMIN F CRAVATT · 2018 to 2026
$9.5M
eDyNAmiC - STANFORDOT2CA278688 · NCI · STANFORD UNIVERSITY · PI PAUL S MISCHEL · 2022 to 2026
$7.7M
Integrated ligand and target discovery by chemical proteomics for glioblastoma treatment.R01CA238249 · NCI · STANFORD UNIVERSITY · PI CRAVATT, BENJAMIN F, MISCHEL, PAUL S · 2021 to 2025
$3.3M
eDyNAmiC - SCRIPPSOT2CA278692 · NCI · SCRIPPS RESEARCH INSTITUTE, THE · PI BENJAMIN F CRAVATT · 2022 to 2026
$2.1M
NCI NIH HHS OT2 CA278688NCI NIH HHS OT2 CA278692NCI NIH HHS R01 CA238249NCI NIH HHS R35 CA231991
6 · The paper itself

Abstract

RNA-binding proteins (RBPs) play important roles in mRNA transcription, processing, and translation. Chemical tools are lacking for RBPs, which has hindered efforts to perturb and understand RBP function in cells. We previously described a chloroacetamide compound (R)-SKBG-1 that covalently binds the RBP NONO and stabilizes its interactions with mRNAs, leading to transcriptional remodeling and suppression of cancer cell growth. Here, we report the crystal structure of an (R)-SKBG-1:NONO complex, which confirms covalent modification of cysteine-145 at a pocket proximal to the RNA-binding interface of the protein. We show that this pocket can also be targeted by a lower reactivity chlorofluoroacetamide analog (R, R)-GL-373, which retains the pharmacological properties of (R)-SKBG-1, including blockade of estrogen receptor expression in breast cancer cells, while displaying much greater proteome-wide selectivity. Our findings thus show that NONO can be targeted by covalent ligands with high specificity to pharmacologically suppress pro-tumorigenic gene products in cancer cells.

Indexed as

AcetamidesRNA-Binding ProteinsCrystallography, X-RayDNA-Binding ProteinsHumansLigandsModels, MolecularAcetamideschloroacetamideDNA-Binding ProteinsLigandsNONO protein, humanRNA-Binding Proteinsactivity-based protein profilingchemical proteomicschlorofluoroacetamidecovalentcysteineNONORNA-binding proteinsstereochemistrytranscriptome

Identifiers

PMID41534524
PMCPMC12918760

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.