Abstract
Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a valid therapeutic target for the treatment of EML4-ALK-positive non-small cell lung cancer (NSCLC). We discovered 12c as a novel and potent EML4-ALK inhibitor through structural optimization of 5a. In mice xenografted with 3T3 cells expressing EML4-ALK, oral administration of 12c demonstrated potent antitumor activity. This article describes the synthesis and biological evaluation of pyrazine-2-carboxamide derivatives along with studies of their structure-activity relationship (SAR) using computational modeling.
Keywords:
Anaplastic lymphoma kinase; Docking study; Echinoderm microtubule-associated protein-like 4; Pyrazine-2-carboxamide; Structure–activity relationship.
Copyright © 2019 Elsevier Ltd. All rights reserved.
MeSH terms
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3T3 Cells
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Amides / chemistry*
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Amides / metabolism
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Amides / pharmacology
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Amides / therapeutic use
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Anaplastic Lymphoma Kinase / antagonists & inhibitors*
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Anaplastic Lymphoma Kinase / genetics
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Anaplastic Lymphoma Kinase / metabolism
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Binding Sites
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Humans
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Mice
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Microtubule-Associated Proteins / antagonists & inhibitors*
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Molecular Docking Simulation
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Neoplasms / drug therapy
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Protein Structure, Tertiary
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Pyrazines / chemistry*
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism
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Solubility
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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Amides
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Antineoplastic Agents
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Cell Cycle Proteins
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Microtubule-Associated Proteins
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Pyrazines
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Recombinant Fusion Proteins
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Anaplastic Lymphoma Kinase
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EML4 protein, human
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Serine Endopeptidases