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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Aurora Kinase A / antagonists & inhibitors*
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Aurora Kinase A / chemistry
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Aurora Kinase A / metabolism
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Body Weight / drug effects
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Drug Design
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Furans / chemistry
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HCT116 Cells
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Heterocyclic Compounds, 2-Ring / chemical synthesis
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Heterocyclic Compounds, 2-Ring / chemistry
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Heterocyclic Compounds, 2-Ring / pharmacology
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Humans
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Ligands
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Lipids / chemistry
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Male
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Mice
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Mice, Nude
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Models, Chemical
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Models, Molecular
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Molecular Structure
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Neoplasms / drug therapy
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Neoplasms / metabolism
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Neoplasms / pathology
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Phenylurea Compounds / chemical synthesis
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Phenylurea Compounds / chemistry
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Phenylurea Compounds / pharmacology
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Structure, Tertiary
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Xenograft Model Antitumor Assays
Substances
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1-(4-(2-((6-(4-(2-(dimethylamino)ethoxy)phenyl)furo(2,3-d)pyrimidin-4-yl)amino)ethyl)phenyl)-3-phenylurea
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Antineoplastic Agents
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Furans
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Heterocyclic Compounds, 2-Ring
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Ligands
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Lipids
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Pyrimidines
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Aurora Kinase A