1. Structure-based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from 4-methylpyridopyrimidinone series.
- Author
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Cheng H, Hoffman JE, Le PT, Pairish M, Kania R, Farrell W, Bagrodia S, Yuan J, Sun S, Zhang E, Xiang C, Dalvie D, and Rahavendran SV
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Binding Sites, Cell Line, Tumor, Crystallography, X-Ray, Humans, Mice, Molecular Docking Simulation, Phosphatidylinositol 3-Kinases metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Structure, Tertiary, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt metabolism, Pyridones chemistry, Pyrimidines chemistry, Pyrimidinones chemical synthesis, Signal Transduction, Structure-Activity Relationship, TOR Serine-Threonine Kinases metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents chemistry, Drug Design, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors chemistry, Pyrimidinones chemistry, TOR Serine-Threonine Kinases antagonists & inhibitors
- Abstract
PI3K, AKT and mTOR, key kinases from a frequently dysregulated PI3K signaling pathway, have been extensively pursued to treat a variety of cancers in oncology. Clinical trials of PF-04691502, a highly potent and selective ATP competitive kinase inhibitor of class 1 PI3Ks and mTOR, from 4-methylpyridopyrimidinone series, led to the discovery of a metabolite with a terminal carboxylic acid, PF-06465603. This paper discusses structure-based drug design, SAR and antitumor activity of the MPP derivatives with a terminal alcohol, a carboxylic acid or a carboxyl amide., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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