Evidence map›Paper›PMID 39994194›Full record

ArticleNature communications2025

Potent and selective SETDB1 covalent negative allosteric modulator reduces methyltransferase activity in cells.

Mélanie Uguen, Devan J Shell, Madhushika Silva, Yu Deng, Fengling Li, Magdalena M Szewczyk, Ka Yang, Yani Zhao, Michael A Stashko, Jacqueline L Norris-Drouin and 16 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing 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

5 citing papers in PubMed.

  1. Article
  2. Article
  3. The Many Faces of SetDB1.Epigenomes · 2026
    Review
  4. Article
  5. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

26 authors.

Mélanie UguenUNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0003-1013-9404
Devan J ShellUNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Madhushika SilvaUniversity of Toronto, Toronto, ON, Canada.ORCID http://orcid.org/0009-0001-7060-0445
Yu DengLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-3264-0809
Fengling LiUniversity of Toronto, Toronto, ON, Canada.
Magdalena M SzewczykUniversity of Toronto, Toronto, ON, Canada.
Ka YangDepartment of Cell Biology, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-8937-7397
Yani ZhaoUNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0009-0007-2779-7290
Michael A StashkoUNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Jacqueline L Norris-DrouinUNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Jarod M WaybrightUNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-5226-8231
Serap BeldarUniversity of Toronto, Toronto, ON, Canada.ORCID http://orcid.org/0000-0002-7601-4543
Justin M RectenwaldUNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Angie L MordantUNC Metabolomics and Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Thomas S WebbUNC Metabolomics and Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Laura E HerringUNC Metabolomics and Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0003-4496-7312
Cheryl H ArrowsmithUniversity of Toronto, Toronto, ON, Canada.
Suzanne AcklooUniversity of Toronto, Toronto, ON, Canada.ORCID http://orcid.org/0000-0002-9696-1839
Steven P GygiDepartment of Cell Biology, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-7626-0034
Robert K McGintyUNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0001-9641-7350
Dalia Barsyte-LovejoyUniversity of Toronto, Toronto, ON, Canada.ORCID http://orcid.org/0000-0002-6560-9621
Pengda LiuLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0003-2755-3601
Levon HalabelianUniversity of Toronto, Toronto, ON, Canada.ORCID http://orcid.org/0000-0003-4361-3619
Lindsey I JamesUNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-6034-7116
Kenneth H PearceUNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0001-8138-5421
Stephen V FryeUNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. svfrye@email.unc.edu.ORCID http://orcid.org/0000-0002-2415-2215

Funding

Virology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Deborah F. Tate · 1985 to 2026
$201.5M
Molecular Mechanisms of Chromatin RecognitionR35GM133498 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Robert McGinty · 2019 to 2026
$3.3M
PROBING ALLOSTERY IN METHYL-LYSINE READER DOMAINSR35GM139514 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI FRYE, STEPHEN VERNON · 2021 to 2025
$2.1M
NCI NIH HHS P30 CA016086NIGMS NIH HHS R35 GM133498NIGMS NIH HHS R35 GM139514U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) P30CA016086U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) R35GM139514
6 · The paper itself

Abstract

A promising drug target, SETDB1, is a dual methyl-lysine (Kme) reader and methyltransferase implicated in cancer and neurodegenerative disease progression. To help understand the role of the triple Tudor domain (3TD) of SETDB1, its Kme reader, we first identify a low micromolar potency small molecule ligand, UNC6535, which occupies simultaneously both the TD2 and TD3 reader binding sites. Further optimization leads to the discovery of UNC10013, a covalent 3TD ligand targeting Cys385 of SETDB1. UNC10013 is potent with a k

Indexed as

Histone-Lysine N-MethyltransferaseAllosteric RegulationBinding SitesHEK293 CellsHumansLigandsMethylationProto-Oncogene Proteins c-aktHistone-Lysine N-MethyltransferaseLigandsProto-Oncogene Proteins c-aktSETDB1 protein, human

Identifiers

PMID39994194
PMCPMC11850789

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
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.