1. 4-methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors.
- Author
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Liu KK, Bagrodia S, Bailey S, Cheng H, Chen H, Gao L, Greasley S, Hoffman JE, Hu Q, Johnson TO, Knighton D, Liu Z, Marx MA, Nambu MD, Ninkovic S, Pascual B, Rafidi K, Rodgers CM, Smith GL, Sun S, Wang H, Yang A, Yuan J, and Zou A
- Subjects
- Administration, Oral, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Cell Line, Tumor, Glioma drug therapy, Humans, Mice, Models, Molecular, Neoplasms drug therapy, Phosphatidylinositol 3-Kinases chemistry, Phosphatidylinositol 3-Kinases metabolism, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors pharmacology, Pteridines administration & dosage, Pteridines pharmacology, Solubility, Structure-Activity Relationship, TOR Serine-Threonine Kinases chemistry, TOR Serine-Threonine Kinases metabolism, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors therapeutic use, Pteridines chemistry, Pteridines therapeutic use, TOR Serine-Threonine Kinases antagonists & inhibitors
- Abstract
Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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