Abstract
Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC(50) = 0.174 μM) during high throughput screening, with selectivity over the related kinase insulin-like growth factor-1 (IGF1R). The X-ray cocrystal structure of 1 with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure-activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R.
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology
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Anaplastic Lymphoma Kinase
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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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Cell Line, Tumor
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Crystallography, X-Ray
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Fluorescence Resonance Energy Transfer
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High-Throughput Screening Assays
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Humans
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Hydrophobic and Hydrophilic Interactions
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Models, Molecular
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Molecular Structure
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Protein Conformation
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor, IGF Type 1 / antagonists & inhibitors
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Amides
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Antineoplastic Agents
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N-(3-(4-morpholinyl)benzyl)-1-(2-((3,4,5-trimethoxyphenyl)amino)-4-pyrimidinyl)-3-piperidinecarboxamide
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Piperidines
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Pyrimidines
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ALK protein, human
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Anaplastic Lymphoma Kinase
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Receptor Protein-Tyrosine Kinases
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Receptor, IGF Type 1