Development of selective inhibitors of phosphatidylinositol 3-kinase C2α.
Nat Chem Biol
; 19(1): 18-27, 2023 01.
Article
in En
| MEDLINE
| ID: mdl-36109648
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phosphatidylinositol 3-Kinases
/
Phosphatidylinositol 3-Kinase
Language:
En
Journal:
Nat Chem Biol
Journal subject:
BIOLOGIA
/
QUIMICA
Year:
2023
Document type:
Article
Affiliation country:
Germany