Structure-based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from 4-methylpyridopyrimidinone series

Autor:	Shaoxian Sun, Phuong Le, Shubha Bagrodia, Sadayappan V. Rahavendran, Eric Zhang, Cheng Hengmiao, Cathy Xiang, Robert Steven Kania, Jing Yuan, William Farrell, Jacqui Elizabeth Hoffman, Pairish Mason Alan, Deepak Dalvie
Rok vydání:	2013
Předmět:	Pyridones Carboxylic acid Metabolite Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Pyrimidinones Pharmacology Crystallography X-Ray Biochemistry Mice Phosphatidylinositol 3-Kinases Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Amide Drug Discovery Animals Humans Structure–activity relationship Protein Kinase Inhibitors Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors chemistry.chemical_classification Binding Sites Kinase Chemistry TOR Serine-Threonine Kinases Organic Chemistry Xenograft Model Antitumor Assays Protein Structure Tertiary Molecular Docking Simulation Pyrimidines Drug Design Molecular Medicine Signal transduction Proto-Oncogene Proteins c-akt Signal Transduction
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 23:2787-2792
ISSN:	0960-894X
DOI:	10.1016/j.bmcl.2013.02.020
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::961a901ccd16f3c3b5c282d7080e9b9e https://doi.org/10.1016/j.bmcl.2013.02.020 Zobrazit plný text záznamu Full Text from ScienceDirect