Abstract
Anaplastic lymphoma kinase (ALK) is a validated therapeutic target for treating echinoderm microtubule-associated protein-like 4 (EML4)-ALK positive non-small cell lung cancer (NSCLC). We synthesized a series of 1,3,5-triazine derivatives and identified ASP3026 (14a) as a potent and selective ALK inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, once-daily oral administration of 14a demonstrated dose-dependent antitumor activity. Here, syntheses and structure-activity relationship (SAR) studies of 1,3,5-triazine derivatives are described.
Keywords:
1,3,5-triazine; anaplastic lymphoma kinase; echinoderm microtubule-associated protein-like 4; non-small cell lung cancer.
MeSH terms
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Administration, Oral
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Anaplastic Lymphoma Kinase
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Animals
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Binding Sites
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Drug Administration Schedule
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Drug Evaluation, Preclinical
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Humans
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Inhibitory Concentration 50
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Lung Neoplasms / drug therapy
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Lung Neoplasms / pathology
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Molecular Docking Simulation
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / therapeutic use
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Protein Structure, Tertiary
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
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Structure-Activity Relationship
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Sulfones / chemical synthesis
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Sulfones / chemistry*
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Sulfones / therapeutic use
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Transplantation, Heterologous
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Triazines / chemical synthesis
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Triazines / chemistry*
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Triazines / therapeutic use
Substances
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ASP3026
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Protein Kinase Inhibitors
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Sulfones
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Triazines
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ALK protein, human
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Alk protein, mouse
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Anaplastic Lymphoma Kinase
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Receptor Protein-Tyrosine Kinases