Abstract
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate.
Copyright © 2011 Elsevier Ltd. All rights reserved.
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 / administration & dosage
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Cell Line, Tumor
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Haplorhini
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Humans
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Lung Neoplasms / drug therapy
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Neoplasms / drug therapy
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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ALK protein, human
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Alk protein, rat
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Anaplastic Lymphoma Kinase
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Receptor Protein-Tyrosine Kinases