Development of selective inhibitors of phosphatidylinositol 3-kinase C2α.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
01 2023
01 2023
Historique:
received:
18
03
2022
accepted:
20
07
2022
pubmed:
16
9
2022
medline:
31
12
2022
entrez:
15
9
2022
Statut:
ppublish
Résumé
Phosphatidylinositol 3-kinase type 2α (PI3KC2α) and related class II PI3K isoforms are of increasing biomedical interest because of their crucial roles in endocytic membrane dynamics, cell division and signaling, angiogenesis, and platelet morphology and function. Herein we report the development and characterization of PhosphatidylInositol Three-kinase Class twO INhibitors (PITCOINs), potent and highly selective small-molecule inhibitors of PI3KC2α catalytic activity. PITCOIN compounds exhibit strong selectivity toward PI3KC2α due to their unique mode of interaction with the ATP-binding site of the enzyme. We demonstrate that acute inhibition of PI3KC2α-mediated synthesis of phosphatidylinositol 3-phosphates by PITCOINs impairs endocytic membrane dynamics and membrane remodeling during platelet-dependent thrombus formation. PITCOINs are potent and selective cell-permeable inhibitors of PI3KC2α function with potential biomedical applications ranging from thrombosis to diabetes and cancer.
Identifiants
pubmed: 36109648
doi: 10.1038/s41589-022-01118-z
pii: 10.1038/s41589-022-01118-z
pmc: PMC7613998
mid: EMS155317
doi:
Substances chimiques
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
Phosphatidylinositols
0
Phosphatidylinositol Phosphates
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
18-27Subventions
Organisme : Medical Research Council
ID : MC_U105184308
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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