Evidence map›Paper›PMID 39414979›Full record

ArticleNature chemical biology2024

Methylarginine targeting chimeras for lysosomal degradation of intracellular proteins.

Laurence J Seabrook, Carolina N Franco, Cody A Loy, Jaida Osman, Callie Fredlender, Jan Zimak, Melissa Campos, Steven T Nguyen, Richard L Watson, Samantha R Levine and 4 more

Abstract read
PubMed Publisher
In one paragraph

Article in Nature chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.

0numbers the graph read from it
0cells of the map it votes in
16citing 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

16 citing papers in PubMed.

  1. Emerging mechanisms of ATG8-independent non-canonical autophagy.Journal of physiology and biochemistry · 2026
    Review
  2. Review
  3. Article
  4. Article
  5. Review
  6. Review
  7. Review
  8. Article
  9. Review
  10. Article
  11. Article
  12. Designing the Proteome with Chemical Tools: Degrons and Beyond.Chembiochem : a European journal of chemical biology · 2025
    Review
  13. Review
  14. Article
  15. Targeted protein degradation with bifunctional molecules as a novel therapeutic modality for Alzheimer's disease & beyond.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025
    Review
  16. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Laurence J SeabrookDepartment of Developmental & Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA.
Carolina N FrancoDepartment of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.
Cody A LoyDepartment of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.ORCID http://orcid.org/0009-0004-9485-3174
Jaida OsmanDepartment of Chemistry, School of Physical Sciences, University of California, Irvine, Irvine, CA, USA.
Callie FredlenderDepartment of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.ORCID http://orcid.org/0009-0001-3836-7444
Jan ZimakCenter for Neurotherapeutics, University of California, Irvine, Irvine, CA, USA.
Melissa CamposDepartment of Developmental & Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA.
Steven T NguyenDepartment of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.
Richard L WatsonDepartment of Medicine, Division of Pulmonary & Critical Care, University of California, Los Angeles, Los Angeles, CA, USA.
Samantha R LevineCenter for Neurotherapeutics, University of California, Irvine, Irvine, CA, USA.ORCID http://orcid.org/0000-0002-0496-9316
Marian F KhalilDepartment of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.
Kaelyn SumigrayDepartment of Genetics, Yale School of Medicine, New Haven, CT, USA.
Darci J TraderDepartment of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.ORCID http://orcid.org/0000-0002-0607-1243
Lauren V AlbrechtDepartment of Developmental & Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA. l.albrecht@uci.edu.ORCID http://orcid.org/0000-0002-3147-8010

Funding

Deciphering Novel Principles of Rapid Proteostatic Control and Innovating Spatiotemporal Lysosomal ToolsR35GM157370 · NIGMS · UNIVERSITY OF CALIFORNIA-IRVINE · PI Lauren Veronica Albrecht · 2024 to 2026
$1.1M
NIGMS NIH HHS R35 GM157370
6 · The paper itself

Abstract

A paradigm shift in drug development is the discovery of small molecules that harness the ubiquitin-proteasomal pathway to eliminate pathogenic proteins. Here we provide a modality for targeted protein degradation in lysosomes. We exploit an endogenous lysosomal pathway whereby protein arginine methyltransferases (PRMTs) initiate substrate degradation via arginine methylation. We developed a heterobifunctional small molecule, methylarginine targeting chimera (MrTAC), that recruits PRMT1 to a target protein for induced degradation in lysosomes. MrTAC compounds degraded substrates across cell lines, timescales and doses. MrTAC degradation required target protein methylation for subsequent lysosomal delivery via microautophagy. A library of MrTAC molecules exemplified the generality of MrTAC to degrade known targets and neo-substrates-glycogen synthase kinase 3β, MYC, bromodomain-containing protein 4 and histone deacetylase 6. MrTAC selectively degraded target proteins and drove biological loss-of-function phenotypes in survival, transcription and proliferation. Collectively, MrTAC demonstrates the utility of endogenous lysosomal proteolysis in the generation of a new class of small molecule degraders.

Indexed as

ArginineLysosomesProtein-Arginine N-MethyltransferasesProteolysisBromodomain Containing ProteinsCell Cycle ProteinsHistone Deacetylase 6HumansMethylationRepressor ProteinsSmall Molecule LibrariesTranscription FactorsArginineBRD4 protein, humanBromodomain Containing ProteinsCell Cycle ProteinsHDAC6 protein, humanHistone Deacetylase 6PRMT1 protein, humanProtein-Arginine N-MethyltransferasesRepressor ProteinsSmall Molecule LibrariesTranscription Factors

Identifiers

PMID39414979

What OpenQuestion holds

Textmetadata
Read underepoch 390

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.