Abstract
A metabolism-based fine-tuning structure-optimization was conducted to address the oxidative metabolism and hERG blockade of our early ALK inhibitor. Compound 8 was identified showing high potency against both ALK wild type and gatekeeper mutant. In addition to the optimal PK properties and significant cell antiproliferative effects, 8 showed complete tumor growth inhibition at doses of 50 or 10mg/kg once daily in the Karpas299 xenograft model. All these results encouraged the further development of 8 as a potent and orally bioavailable ALK inhibitor.
Keywords:
Antitumor activity; Benzo[b]carbazolone; EML4-ALK kinase; Oxidative metabolism; hERG.
Copyright © 2016 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 / chemistry*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Benzene Derivatives / chemistry*
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Benzene Derivatives / pharmacokinetics
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Benzene Derivatives / pharmacology*
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Benzene Derivatives / therapeutic use
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Cell Line, Tumor
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Drug Discovery
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Humans
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Mice
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NIH 3T3 Cells
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Neoplasms / drug therapy
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Neoplasms / enzymology
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Neoplasms / metabolism
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Oxidation-Reduction
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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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Protein Kinase Inhibitors / therapeutic use
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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
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Transcriptional Regulator ERG / metabolism
Substances
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Antineoplastic Agents
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Benzene Derivatives
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ERG protein, human
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Protein Kinase Inhibitors
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Transcriptional Regulator ERG
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ALK protein, human
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Alk protein, mouse
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Alk protein, rat
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Anaplastic Lymphoma Kinase
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Receptor Protein-Tyrosine Kinases