Abstract
In this study, a series of novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety was described for ALK inhibitor. The pyrazole, imidazole, 1,2,4-triazole, piperazine and phenanthridine moieties were employed at the 2-position of pyrimidine. Among the compounds synthesized, 28, 29, 36, and 42 showed promising anti-ALK activities in enzymatic- and cell-based assays. In vivo H3122 xenograft model study showed that compound 29 effectively suppressed ALK-driven tumor growth, similar to the extent of ceritinib, suggesting that it could be used for a novel ALK inhibitor development.
Keywords:
2,4-Diaminopyrimidine; Anaplastic lymphoma kinase; Cancer; Fused tricyclic moiety.
Copyright © 2017. Published by Elsevier Ltd.
MeSH terms
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Administration, Oral
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Anaplastic Lymphoma Kinase
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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 / therapeutic use
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Antineoplastic Agents / toxicity
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Humans
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Inhibitory Concentration 50
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Lung Neoplasms / drug therapy
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Mice
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Mice, SCID
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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 Kinase Inhibitors / toxicity
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / therapeutic use
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Pyrimidines / toxicity
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
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Transplantation, Heterologous
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyrimidines
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2,4-diaminopyrimidine
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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