Metabolism-driven in vitro/in vivo disconnect of an oral ERɑ VHL-PROTAC.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
13 May 2024
13 May 2024
Historique:
received:
17
01
2024
accepted:
24
04
2024
medline:
14
5
2024
pubmed:
14
5
2024
entrez:
13
5
2024
Statut:
epublish
Résumé
Targeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro-in vivo disconnect. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs.
Identifiants
pubmed: 38740899
doi: 10.1038/s42003-024-06238-x
pii: 10.1038/s42003-024-06238-x
doi:
Substances chimiques
Estrogen Receptor alpha
0
Von Hippel-Lindau Tumor Suppressor Protein
EC 2.3.2.27
VHL protein, human
EC 6.3.2.-
ESR1 protein, human
0
Antineoplastic Agents
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
563Informations de copyright
© 2024. The Author(s).
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