title: Development of first lead structures for phosphoinositide 3-kinase-C2γ inhibitors.
abstract: The importance of complete elucidation of the biological functions of phosphoinositide 3-kinases (PI3K) was realized years ago. They generate 3-phosphoinositides, which are known to function as important second messengers in many inter- and intracellular signaling pathways. However, the functional role of class II PI3Ks is still unclear. Herein, we describe the synthesis of a panel of compounds that were tested against all eight mammalian PI3K-isoforms. We found inhibitors with some selectivity for class II PI3K-C2γ and also compounds with preferred inhibition of class II PI3K-C2β, providing structural leads to develop selective tool compounds.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls University Tuebingen , Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Freitag
authors.forename: Prajwal
authors.initials: P
authors.lastname: Prajwal
authors.forename: Aliaksei
authors.initials: A
authors.lastname: Shymanets
authors.forename: Christian
authors.initials: C
authors.lastname: Harteneck
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
authors.forename: Christoph
authors.initials: C
authors.lastname: Schächtele
authors.forename: Michael
authors.initials: M
authors.lastname: Kubbutat
authors.forename: Frank
authors.initials: F
authors.lastname: Totzke
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Laufer
mesh_terms: D000818:Animals; D058541:Class II Phosphatidylinositol 3-Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D058541:Class II Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D013449:Sulfonamides; D000096926:Benzenesulfonamides