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From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome
- Source :
- ACS Medicinal Chemistry Letters. 8:1093-1098
- Publication Year :
- 2017
- Publisher :
- American Chemical Society (ACS), 2017.
-
Abstract
- Selective inhibitors of phosphoinositide 3-kinase delta are of interest for the treatment of inflammatory diseases. Initial optimization of a 3-substituted indazole hit compound targeting the kinase PIM1 focused on improving selectivity over GSK3β through consideration of differences in the ATP binding pockets. Continued kinase cross-screening showed PI3Kδ activity in a series of 4,6-disubstituted indazole compounds, and subsequent structure-activity relationship exploration led to the discovery of an indole-containing lead compound as a potent PI3Kδ inhibitor with selectivity over the other PI3K isoforms.
- Subjects :
- 0301 basic medicine
Gene isoform
Indazole
Kinase
Organic Chemistry
PIM1
Biology
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
030104 developmental biology
0302 clinical medicine
chemistry
030220 oncology & carcinogenesis
Drug Discovery
Kinome
Selectivity
Lead compound
PI3K/AKT/mTOR pathway
Subjects
Details
- ISSN :
- 19485875
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- ACS Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....27f5519d38d282f0bd73dd26004a6f3a