Identification of allosteric binding sites for PI3Kα oncogenic mutant specific inhibitor design

Autor:	Sandra B. Gabelli, Kenneth W. Kinzler, S. Maheshwari, L. Mario Amzel, Bert Vogelstein, Fiona M. McRobb, Michelle S. Miller
Rok vydání:	2017
Předmět:	Models Molecular 0301 basic medicine Class I Phosphatidylinositol 3-Kinases Protein subunit Clinical Biochemistry Fragment-based lead discovery Allosteric regulation Mutant Binding pocket Pharmaceutical Science Crystallography X-Ray Biochemistry Article Phosphatidylinositol 3-Kinases Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Discovery Humans Phosphatidylinositol Protein Kinase Inhibitors Molecular Biology Gene PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Genetics Dose-Response Relationship Drug Molecular Structure Organic Chemistry 030104 developmental biology chemistry Drug Design 030220 oncology & carcinogenesis Mutation Molecular Medicine Mutant Proteins Allosteric Site
Zdroj:	Bioorganic & Medicinal Chemistry. 25:1481-1486
ISSN:	0968-0896
DOI:	10.1016/j.bmc.2017.01.012
Popis:	PIK3CA , the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kα could maximize treatment efficiency while minimizing side-effects. Herein we describe the identification of novel binding pockets that may provide an opportunity for the design of mutant selective inhibitors. Using a fragment-based approach, we screened a library of 352 fragments (MW
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b8e22884764788db22824013d69e3e90 https://doi.org/10.1016/j.bmc.2017.01.012 Zobrazit plný text záznamu Full Text from ScienceDirect