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Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2011 Dec 22; Vol. 54 (24), pp. 8328-42. Date of Electronic Publication: 2011 Nov 23. - Publication Year :
- 2011
-
Abstract
- Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice.
- Subjects :
- Adenosine Triphosphate chemistry
Animals
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Binding Sites
Biological Availability
Cell Line, Tumor
Checkpoint Kinase 1
Crystallography, X-Ray
Drug Screening Assays, Antitumor
Humans
Isoquinolines chemistry
Isoquinolines pharmacology
Mice
Mice, Nude
Molecular Conformation
Neoplasm Transplantation
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Pyrazines chemistry
Pyrazines pharmacology
Pyridines chemistry
Pyridines pharmacology
Stereoisomerism
Structure-Activity Relationship
Transplantation, Heterologous
Antineoplastic Agents chemical synthesis
Isoquinolines chemical synthesis
Protein Kinase Inhibitors chemical synthesis
Protein Kinases metabolism
Pyrazines chemical synthesis
Pyridines chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 54
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22111927
- Full Text :
- https://doi.org/10.1021/jm2007326