Abstract
A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.
MeSH terms
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Animals
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Biological Availability
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Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
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Class I Phosphatidylinositol 3-Kinases / physiology
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Crystallography, X-Ray
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Drug Design
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Female
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Humans
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Indazoles / chemical synthesis
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Indazoles / pharmacokinetics
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Indazoles / pharmacology
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Mice
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Mice, Nude
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Microsomes, Liver / metabolism
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Models, Molecular
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Piperazines / chemical synthesis*
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Proto-Oncogene Proteins c-akt / physiology
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Purines / chemical synthesis
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Purines / pharmacokinetics
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Purines / pharmacology
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Pyrazoles / chemical synthesis
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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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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Signal Transduction
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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Sulfones / chemical synthesis
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Sulfones / pharmacokinetics
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Sulfones / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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Triazines / chemical synthesis*
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Triazines / pharmacokinetics
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Triazines / pharmacology
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Xenograft Model Antitumor Assays
Substances
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4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine
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Indazoles
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Piperazines
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Purines
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Pyrazoles
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Pyridines
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Pyrimidines
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Sulfonamides
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Sulfones
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Triazines
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Class I Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases