title: Potent and highly selective benzimidazole inhibitors of PI3-kinase delta.
abstract: Inhibition of PI3Kδ is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective benzimidazole-based inhibitors of PI3Kδ. These inhibitors do not occupy the selectivity pocket between Trp760 and Met752 that is induced by other families of PI3Kδ inhibitors. Instead, the selectivity of the compounds for inhibition of PI3Kδ relative to other PI3K isoforms appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3Kδ binding pocket. The pharmacokinetic properties and the ability of compound 5 to inhibit the function of B-cells in vivo are described.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. murray.jeremy@gene.com
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Murray
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Chan
authors.forename: Mercedesz
authors.initials: M
authors.lastname: Balazs
authors.forename: Erin
authors.initials: E
authors.lastname: Bradley
authors.forename: Georgette
authors.initials: G
authors.lastname: Castanedo
authors.forename: Christine
authors.initials: C
authors.lastname: Chabot
authors.forename: David
authors.initials: D
authors.lastname: Chantry
authors.forename: Michael
authors.initials: M
authors.lastname: Flagella
authors.forename: David M
authors.initials: DM
authors.lastname: Goldstein
authors.forename: Rama
authors.initials: R
authors.lastname: Kondru
authors.forename: John
authors.initials: J
authors.lastname: Lesnick
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Lucas
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.forename: Stephen
authors.initials: S
authors.lastname: Price
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Brian
authors.initials: B
authors.lastname: Safina
authors.forename: Pascal P A
authors.initials: PP
authors.lastname: Savy
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Seward
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet
chemical_list: D001562:Benzimidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors