Abstract
Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378.
Keywords:
ALK; Cancer; LDK378; NSCLC; Tetrahydroisoquinoline (THIQ).
Copyright © 2015 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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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 Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Female
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Humans
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Mice
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Mice, Nude
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / pathology
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Rats
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
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Structure-Activity Relationship
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Tetrahydroisoquinolines / chemistry
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Tetrahydroisoquinolines / pharmacology*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Pyrimidines
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Tetrahydroisoquinolines
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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