Abstract
Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhibitor crizotinib. Through a series of targeted modifications on an ALK inhibitor diaminopyrimidine scaffold, our research group has driven improvements in ALK potency, kinase selectivity, and overall pharmaceutical properties. Optimization of this scaffold has led to the identification of a potent and efficacious inhibitor of ALK, 25b. A striking feature of 25b over previously described ALK inhibitors is its >600-fold selectivity over insulin receptor (IR), a closely related kinase family member. Most importantly, 25b exhibited dose proportional escalation in rat compared to compound 3 which suffered dose limiting absorption preventing further advancement. Compound 25b exhibited significant in vivo antitumor efficacy when dosed orally in an ALK-positive ALCL tumor xenograft model in SCID mice, warranting further assessment in advanced preclinical models.
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 / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cycloheptanes / chemical synthesis*
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Cycloheptanes / pharmacokinetics
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Cycloheptanes / pharmacology
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Dogs
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Dose-Response Relationship, Drug
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Female
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Humans
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Lymphoma, Large-Cell, Anaplastic / drug therapy
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Mice
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Mice, SCID
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Models, Molecular
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Morpholines / chemical synthesis
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Morpholines / pharmacokinetics
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Morpholines / pharmacology
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Phosphorylation
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Piperazines / chemical synthesis
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Protein Binding
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Pyrimidines / chemical synthesis
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Rats
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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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Receptor, Insulin / antagonists & inhibitors
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Cycloheptanes
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Morpholines
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Piperazines
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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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Receptor, Insulin