title: Synthesis and structure-activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors.
abstract: A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.
authors.affiliation: Cancer Metabolism Chemistry, GlaxoSmithKline, Collegeville, PA 19426-0989, United States. hong.2.lin@gsk.com
authors.forename: Hong
authors.initials: H
authors.lastname: Lin
authors.forename: Karl
authors.initials: K
authors.lastname: Erhard
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Hardwicke
authors.forename: Juan I
authors.initials: JI
authors.lastname: Luengo
authors.forename: James F
authors.initials: JF
authors.lastname: Mack
authors.forename: Jeanelle
authors.initials: J
authors.lastname: McSurdy-Freed
authors.forename: Ramona
authors.initials: R
authors.lastname: Plant
authors.forename: Kaushik
authors.initials: K
authors.lastname: Raha
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Rominger
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sanchez
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schaber
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Schulz
authors.forename: Michael D
authors.initials: MD
authors.lastname: Spengler
authors.forename: Rosanna
authors.initials: R
authors.lastname: Tedesco
authors.forename: Ren
authors.initials: R
authors.lastname: Xie
authors.forename: Jin J
authors.initials: JJ
authors.lastname: Zeng
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Rivero
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D058539:Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human