Abstract
In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.
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 / pharmacology*
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / enzymology
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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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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Drug Screening Assays, Antitumor
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Female
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / enzymology
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Lung Neoplasms / pathology
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Mice
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Mice, SCID
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Molecular Conformation
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / pathology
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Organophosphorus Compounds / administration & dosage
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Organophosphorus Compounds / chemistry
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Organophosphorus Compounds / pharmacology*
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Phosphines / chemistry*
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Phosphines / pharmacology
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Pyrimidines / administration & dosage
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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 / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Organophosphorus Compounds
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Phosphines
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Protein Kinase Inhibitors
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Pyrimidines
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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
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phosphine
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brigatinib