Paralogue-Selective Degradation of the Lysine Acetyltransferase EP300.
Journal
JACS Au
ISSN: 2691-3704
Titre abrégé: JACS Au
Pays: United States
ID NLM: 101775714
Informations de publication
Date de publication:
26 Aug 2024
26 Aug 2024
Historique:
received:
16
05
2024
revised:
05
07
2024
accepted:
05
07
2024
medline:
1
9
2024
pubmed:
1
9
2024
entrez:
30
8
2024
Statut:
epublish
Résumé
The transcriptional coactivators EP300 and CREBBP are critical regulators of gene expression that share high sequence identity but exhibit nonredundant functions in basal and pathological contexts. Here, we report the development of a bifunctional small molecule, MC-1, capable of selectively degrading EP300 over CREBBP. Using a potent aminopyridine-based inhibitor of the EP300/CREBBP catalytic domain in combination with a VHL ligand, we demonstrate that MC-1 preferentially degrades EP300 in a proteasome-dependent manner. Mechanistic studies reveal that selective degradation cannot be predicted solely by target engagement or ternary complex formation, suggesting additional factors govern paralogue-specific degradation. MC-1 inhibits cell proliferation in a subset of cancer cell lines and provides a new tool to investigate the noncatalytic functions of EP300 and CREBBP. Our findings expand the repertoire of EP300/CREBBP-targeting chemical probes and offer insights into the determinants of selective degradation of highly homologous proteins.
Identifiants
pubmed: 39211607
doi: 10.1021/jacsau.4c00442
pmc: PMC11350577
doi:
Types de publication
Journal Article
Langues
eng
Pagination
3094-3103Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC011488
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2024 The Authors. Published by American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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