Abstract
Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4+/-0.6 nM, Akt cell potency of 50+/-19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po).
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Combinatorial Chemistry Techniques
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Crystallography, X-Ray
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Disease Models, Animal
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Drug Design
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Inhibitory Concentration 50
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Mice
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Molecular Conformation
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Molecular Structure
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology*
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Pyrimidines
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Pyrroles
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Spiro Compounds
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Proto-Oncogene Proteins c-akt