Abstract
The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, Q252H, Y253H, E255K, E255V, F317L, and M351T in biochemical and cellular assays. In addition, compound 2 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. Compound 2 is among the first type-II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design the third generation Bcr-Abl kinase inhibitors.
MeSH terms
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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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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Line, Tumor
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Cell Proliferation
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Drug Screening Assays, Antitumor
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Female
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Fusion Proteins, bcr-abl / antagonists & inhibitors*
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Fusion Proteins, bcr-abl / genetics
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Humans
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Male
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Mice
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Mice, Inbred BALB C
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Mice, SCID
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Models, Molecular
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Mutation
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Neoplasm Transplantation
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Phosphorylation
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / genetics
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Pyrimidinones / chemical synthesis*
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Pyrimidinones / pharmacokinetics
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Pyrimidinones / pharmacology
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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Antineoplastic Agents
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Bridged Bicyclo Compounds, Heterocyclic
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N-(4-methyl-3-(1-methyl-7-(6-methylpyridin-3-ylamino)-2-oxo-1,2-dihydropyrimido(4,5-d)pyrimidin-3(4H)-yl)phenyl)-3-(trifluoromethyl)benzamide
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Pyrimidines
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Pyrimidinones
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Protein-Tyrosine Kinases
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Fusion Proteins, bcr-abl