title: The design and identification of brain penetrant inhibitors of phosphoinositide 3-kinase α.
abstract: Inhibition of phosphoinositide 3-kinase (PI3K) signaling through PI3Kα has received significant attention for its potential in cancer therapy. While the PI3K pathway is a well-established and widely pursued target for the treatment of many cancer types due to the high frequency of abnormal PI3K signaling, glioblastoma multiforme (GBM) is particularly relevant because the pathway is implicated in more than 80% of GBM cases. Herein, we report the identification of PI3K inhibitors designed to cross the blood-brain barrier (BBB) to engage their target where GBM tumors reside. We leveraged our historical experience with PI3K inhibitors to identify correlations between physicochemical properties and transporter efflux as well as metabolic stability to focus the selection of molecules for further study.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. theffron@gene.com
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Bruno
authors.initials: B
authors.lastname: Alicke
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cheong
authors.forename: Jennafer
authors.initials: J
authors.lastname: Dotson
authors.forename: Kyle
authors.initials: K
authors.lastname: Edgar
authors.forename: Richard
authors.initials: R
authors.lastname: Goldsmith
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Lee
authors.forename: John D
authors.initials: JD
authors.lastname: Lesnick
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
authors.forename: Chudi
authors.initials: C
authors.lastname: Ndubaku
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Alan G
authors.initials: AG
authors.lastname: Olivero
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.forename: Emile G
authors.initials: EG
authors.lastname: Plise
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.forename: Sean
authors.initials: S
authors.lastname: Trapp
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wallin
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D010539:Permeability; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013499:Surface Properties
chemical_list: D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors