title: Imidazo[1,5-a]pyrazines: orally efficacious inhibitors of mTORC1 and mTORC2.
abstract: The discovery and optimization of a series of imidazo[1,5-a]pyrazine inhibitors of mTOR is described. HTS hits were optimized for potency, selectivity and metabolic stability to provide the orally bioavailable proof of concept compound 4c that demonstrated target inhibition in vivo and concomitant inhibition of tumor growth in an MDA-MB-231 xenograft model.
authors.affiliation: OSI Oncology, OSI Pharmaceuticals, Inc, 1 Bioscience Park Drive, Farmingdale, NY 11735, USA. acrew@osip.com
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Crew
authors.forename: Shripad V
authors.initials: SV
authors.lastname: Bhagwat
authors.forename: Hanqing
authors.initials: H
authors.lastname: Dong
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bittner
authors.forename: Anna
authors.initials: A
authors.lastname: Chan
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Heather
authors.initials: H
authors.lastname: Coate
authors.forename: Andrew
authors.initials: A
authors.lastname: Cooke
authors.forename: Prafulla C
authors.initials: PC
authors.lastname: Gokhale
authors.forename: Ayako
authors.initials: A
authors.lastname: Honda
authors.forename: Meizhong
authors.initials: M
authors.lastname: Jin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kahler
authors.forename: Christine
authors.initials: C
authors.lastname: Mantis
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mulvihill
authors.forename: Paula A
authors.initials: PA
authors.lastname: Tavares-Greco
authors.forename: Brian
authors.initials: B
authors.lastname: Volk
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Werner
authors.forename: Lee D
authors.initials: LD
authors.lastname: Arnold
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Pachter
authors.forename: Robert
authors.initials: R
authors.lastname: Wild
authors.forename: Neil W
authors.initials: NW
authors.lastname: Gibson
mesh_terms: D000284:Administration, Oral; D045744:Cell Line, Tumor; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008958:Models, Molecular; D046912:Multiprotein Complexes; D011506:Proteins / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C493245:CRTC2 protein, human; D007093:Imidazoles; D046912:Multiprotein Complexes; D011506:Proteins; D011719:Pyrazines; D014157:Transcription Factors; C517813:imidazo(1,5-a)pyrazine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases