Sauveur-Michel Maira1, Charles Voliva, Carlos Garcia-Echeverria. 1. Novartis Institutes for Biomedical Research (NIBR) Oncology, Novartis Pharma AG, Klybeckstrasse, WKL-125.1.08, CH-4002 Basel, Switzerland. sauveur-michel.maira@novartis.com
Abstract
BACKGROUND: A substantial number of epidemiologic and experimental studies support an important role for Class I phosphatidylinositol 3-kinases (PI3Ks) in the biology of human cancer. OBJECTIVE: This article reviews the authors' understanding of the role of Class IA PI3K in the biology of human cancers and present discovery efforts to identify and develop inhibitors of this class of lipid kinases. METHODS: Books, journals, databases and websites have been searched to find the latest information on the subject. RESULTS/ CONCLUSIONS: In spite of the progress made over the past few years, more studies are still needed to better understand the biology of this pathway, its interaction(s) with other signaling cascades, and the role of the individual paralogs and PI3Kalpha mutants in human cancer. From a drug discovery perspective, medicinal chemistry efforts have led to the discovery of new pan-PI3K and isoform selective inhibitors with improved specificity, potency and pharmaceutical properties. Phase I clinical studies have been initiated with some of these PI3K inhibitors and the efficacy and therapeutic index of this new generation of anticancer agents is eagerly awaited.
BACKGROUND: A substantial number of epidemiologic and experimental studies support an important role for Class I phosphatidylinositol 3-kinases (PI3Ks) in the biology of humancancer. OBJECTIVE: This article reviews the authors' understanding of the role of Class IA PI3K in the biology of humancancers and present discovery efforts to identify and develop inhibitors of this class of lipid kinases. METHODS: Books, journals, databases and websites have been searched to find the latest information on the subject. RESULTS/ CONCLUSIONS: In spite of the progress made over the past few years, more studies are still needed to better understand the biology of this pathway, its interaction(s) with other signaling cascades, and the role of the individual paralogs and PI3Kalpha mutants in humancancer. From a drug discovery perspective, medicinal chemistry efforts have led to the discovery of new pan-PI3K and isoform selective inhibitors with improved specificity, potency and pharmaceutical properties. Phase I clinical studies have been initiated with some of these PI3K inhibitors and the efficacy and therapeutic index of this new generation of anticancer agents is eagerly awaited.
Authors: Ayako Honda; Edmund Harrington; Ivan Cornella-Taracido; Pascal Furet; Mark S Knapp; Meir Glick; Ellen Triantafellow; William E Dowdle; Dmitri Wiedershain; Wieslawa Maniara; Christine Moore; Peter M Finan; Lawrence G Hamann; Brant Firestone; Leon O Murphy; Erin P Keaney Journal: ACS Med Chem Lett Date: 2015-11-13 Impact factor: 4.345
Authors: Klemens Hoegenauer; Nicolas Soldermann; Frédéric Stauffer; Pascal Furet; Nadege Graveleau; Alexander B Smith; Christina Hebach; Gregory J Hollingworth; Ian Lewis; Sascha Gutmann; Gabriele Rummel; Mark Knapp; Romain M Wolf; Joachim Blanz; Roland Feifel; Christoph Burkhart; Frédéric Zécri Journal: ACS Med Chem Lett Date: 2016-06-02 Impact factor: 4.345