Abstract
Anaplastic lymphoma kinase (ALK) is a promising new target for therapy of certain cancers such as anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT). We have identified a series of novel pyridones as kinase inhibitors of ALK by application of a stepwise process involving in vitro screening of a novel targeted library followed by iterative template modification based on medicinal chemistry insights and computational ranking of virtual libraries. Using this process, we discovered ALK-selective inhibitors with improved potency and selectivity. Herein the details of the design process and synthesis of these novel pyridones, along with their enzymatic and cell-based activity, are discussed.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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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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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Cell Line, Tumor
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Cell Survival / drug effects
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Combinatorial Chemistry Techniques
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Databases, Factual
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Drug Design
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Humans
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Mice
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Models, Molecular
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Pyridones / chemical synthesis*
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Pyridones / chemistry
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Pyridones / pharmacology
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Receptor Protein-Tyrosine Kinases
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Structure-Activity Relationship
Substances
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Amides
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Antineoplastic Agents
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Pyridones
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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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Protein-Tyrosine Kinases
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Receptor Protein-Tyrosine Kinases