Abstract
We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Aminopyridines
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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 / pharmacology
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / genetics
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Brain Neoplasms / secondary*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm / drug effects*
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Humans
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Lactams
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Lactams, Macrocyclic / administration & dosage*
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Lactams, Macrocyclic / pharmacology
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Mice
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Mutation
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NIH 3T3 Cells
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Neoplasms / drug therapy*
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Neoplasms / genetics
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / pharmacology
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Pyrazoles
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / genetics*
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Xenograft Model Antitumor Assays
Substances
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Aminopyridines
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Antineoplastic Agents
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Lactams
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Lactams, Macrocyclic
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Protein Kinase Inhibitors
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Pyrazoles
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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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Receptor Protein-Tyrosine Kinases
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lorlatinib