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Optimization of ligand and lipophilic efficiency to identify an in vivo active furano-pyrimidine Aurora kinase inhibitor.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2013 Jul 11; Vol. 56 (13), pp. 5247-60. Date of Electronic Publication: 2013 Jun 28. - Publication Year :
- 2013
-
Abstract
- Ligand efficiency (LE) and lipophilic efficiency (LipE) are two important indicators of "drug-likeness", which are dependent on the molecule's activity and physicochemical properties. We recently reported a furano-pyrimidine Aurora kinase inhibitor 4 (LE = 0.25; LipE = 1.75), with potent activity in vitro; however, 4 was inactive in vivo. On the basis of insights obtained from the X-ray co-crystal structure of the lead 4, various solubilizing functional groups were introduced to optimize both the activity and physicochemical properties. Emphasis was placed on identifying potential leads with improved activity as well as better LE and LipE by exercising tight control over the molecular weight and lipophilicity of the molecules. Rational optimization has led to the identification of Aurora kinase inhibitor 27 (IBPR001; LE = 0.26; LipE = 4.78), with improved in vitro potency and physicochemical properties, resulting in an in vivo active (HCT-116 colon cancer xenograft mouse model) anticancer agent.
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Aurora Kinase A chemistry
Aurora Kinase A metabolism
Body Weight drug effects
Cell Proliferation drug effects
Crystallography, X-Ray
Drug Design
Furans chemistry
HCT116 Cells
Heterocyclic Compounds, 2-Ring chemical synthesis
Heterocyclic Compounds, 2-Ring chemistry
Heterocyclic Compounds, 2-Ring pharmacology
Humans
Ligands
Lipids chemistry
Male
Mice
Mice, Nude
Models, Chemical
Models, Molecular
Molecular Structure
Neoplasms drug therapy
Neoplasms metabolism
Neoplasms pathology
Phenylurea Compounds chemical synthesis
Phenylurea Compounds chemistry
Phenylurea Compounds pharmacology
Protein Binding
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Protein Structure, Tertiary
Pyrimidines chemical synthesis
Pyrimidines chemistry
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Aurora Kinase A antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 56
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23808327
- Full Text :
- https://doi.org/10.1021/jm4006059