title: The design, synthesis, and biological evaluation of PIM kinase inhibitors.
abstract: A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.
authors.affiliation: Exelixis, Department of Drug Discovery, South San Francisco, CA 94080, USA. alew@exelixis.com
authors.forename: Amy Lew
authors.initials: AL
authors.lastname: Tsuhako
authors.forename: David S
authors.initials: DS
authors.lastname: Brown
authors.forename: Elena S
authors.initials: ES
authors.lastname: Koltun
authors.forename: Naing
authors.initials: N
authors.lastname: Aay
authors.forename: Arlyn
authors.initials: A
authors.lastname: Arcalas
authors.forename: Vicky
authors.initials: V
authors.lastname: Chan
authors.forename: Hongwang
authors.initials: H
authors.lastname: Du
authors.forename: Stefan
authors.initials: S
authors.lastname: Engst
authors.forename: Maurizio
authors.initials: M
authors.lastname: Franzini
authors.forename: Adam
authors.initials: A
authors.lastname: Galan
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.forename: Stuart
authors.initials: S
authors.lastname: Johnston
authors.forename: Brian
authors.initials: B
authors.lastname: Kane
authors.forename: Moon H
authors.initials: MH
authors.lastname: Kim
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Laird
authors.forename: Rui
authors.initials: R
authors.lastname: Lin
authors.forename: Lillian
authors.initials: L
authors.lastname: Mock
authors.forename: Iris
authors.initials: I
authors.lastname: Ngan
authors.forename: Michael
authors.initials: M
authors.lastname: Pack
authors.forename: Gordon
authors.initials: G
authors.lastname: Stott
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Stout
authors.forename: Peiwen
authors.initials: P
authors.lastname: Yu
authors.forename: Cristiana
authors.initials: C
authors.lastname: Zaharia
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhang
authors.forename: Peiwen
authors.initials: P
authors.lastname: Zhou
authors.forename: John M
authors.initials: JM
authors.lastname: Nuss
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Kearney
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D005663:Furans / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D005663:Furans; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim