Design of selective PI3Kα inhibitors starting from a promiscuous pan kinase scaffold.
Bioorg Med Chem Lett
; 25(13): 2679-85, 2015 Jul 01.
Article
in En
| MEDLINE
| ID: mdl-25980912
ABSTRACT
Starting from compound 1, a potent PI3Kα inhibitor having poor general kinase selectivity, we used structural data and modelling to identify key exploitable differences between PI3Kα and the other kinases. This approach led us to design chemical modifications of the central pyrazole, which solved the poor kinase selectivity seen as a strong liability for the initial compound 1. Amongst the modifications explored, a 1,3,4-triazole ring (as in compound 4) as a replacement of the initial pyrazole provided good potency against PI3Kα, with excellent kinase selectivity.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Enzyme Inhibitors
/
Phosphoinositide-3 Kinase Inhibitors
Limits:
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2015
Document type:
Article