Abstract
Recent reports suggest that an increasing number of patients with lung cancer, especially those with activating mutations of the epidermal growth factor receptor (EGFR), also present with brain metastases and leptomeningeal metastases. These patients have poor prognosis as there are no approved drugs for these indications. Available agents have poor efficacy for these patients even at well above their standard dose. Herein, we report the discovery of (4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (2R)-2,4-dimethylpiperazine-1-carboxylate 1m (AZD3759), an investigational drug currently in Phase 1 clinical trial, which has excellent central nervous system penetration and which induces profound regression of brain metastases in a mouse model.
MeSH terms
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Animals
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Brain / diagnostic imaging
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Brain / metabolism
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Brain Neoplasms / drug therapy
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Brain Neoplasms / secondary
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Central Nervous System / metabolism*
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Clinical Trials, Phase I as Topic
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Dogs
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Drug Discovery
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ErbB Receptors / antagonists & inhibitors*
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Macaca fascicularis
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Male
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Mice
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Piperazines / chemical synthesis
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Piperazines / pharmacology*
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Piperazines / therapeutic use
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Positron-Emission Tomography
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Quinazolines / chemical synthesis
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Quinazolines / pharmacology*
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Quinazolines / therapeutic use
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Rats
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Rats, Wistar
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Xenograft Model Antitumor Assays
Substances
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AZD3759
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Piperazines
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Protein Kinase Inhibitors
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Quinazolines
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ErbB Receptors
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Protein-Tyrosine Kinases