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Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2012 May 24; Vol. 55 (10), pp. 4580-93. Date of Electronic Publication: 2012 May 07. - Publication Year :
- 2012
-
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.
- Subjects :
- Administration, Oral
Anaplastic Lymphoma Kinase
Animals
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents pharmacology
Cell Line, Tumor
Cycloheptanes pharmacokinetics
Cycloheptanes pharmacology
Dogs
Dose-Response Relationship, Drug
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels antagonists & inhibitors
Female
Humans
Lymphoma, Large-Cell, Anaplastic drug therapy
Mice
Mice, SCID
Models, Molecular
Morpholines chemical synthesis
Morpholines pharmacokinetics
Morpholines pharmacology
Phosphorylation
Piperazines chemical synthesis
Piperazines pharmacokinetics
Piperazines pharmacology
Protein Binding
Pyrimidines chemical synthesis
Pyrimidines pharmacokinetics
Pyrimidines pharmacology
Rats
Rats, Sprague-Dawley
Receptor Protein-Tyrosine Kinases metabolism
Receptor, Insulin antagonists & inhibitors
Structure-Activity Relationship
Xenograft Model Antitumor Assays
Antineoplastic Agents chemical synthesis
Cycloheptanes chemical synthesis
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 55
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22564207
- Full Text :
- https://doi.org/10.1021/jm201550q