title: Hit to lead account of the discovery of a new class of inhibitors of Pim kinases and crystallographic studies revealing an unusual kinase binding mode.
abstract: A series of inhibitors of Pim-2 kinase identified by high-throughput screening is described. Details of the hit validation and lead generation process and structure-activity relationship (SAR) studies are presented. Disclosure of an unconventional binding mode for 1, as revealed by X-ray crystallography using the highly homologous Pim-1 protein, is also presented, and observed binding features are shown to correlate with the Pim-2 SAR. While highly selective within the kinase family, the series shows similar potency for both Pim-1 and Pim-2, which was expected on the basis of homology, but unusual in light of reports in the literature documenting a bias for Pim-1. A rationale for these observations based on Pim-1 and Pim-2 K(M(ATP)) values is suggested. Some interesting cross reactivity with casein kinase-2 was also identified, and structural features which may contribute to the association are discussed.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut 06801-0368, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Qian
authors.forename: Lian
authors.initials: L
authors.lastname: Wang
authors.forename: Charles L
authors.initials: CL
authors.lastname: Cywin
authors.forename: Bennett T
authors.initials: BT
authors.lastname: Farmer
authors.forename: Eugene
authors.initials: E
authors.lastname: Hickey
authors.forename: Carol
authors.initials: C
authors.lastname: Homon
authors.forename: Scott
authors.initials: S
authors.lastname: Jakes
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Kashem
authors.forename: George
authors.initials: G
authors.lastname: Lee
authors.forename: Scott
authors.initials: S
authors.lastname: Leonard
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Ronald
authors.initials: R
authors.lastname: Magboo
authors.forename: Wang
authors.initials: W
authors.lastname: Mao
authors.forename: Edward
authors.initials: E
authors.lastname: Pack
authors.forename: Charlene
authors.initials: C
authors.lastname: Peng
authors.forename: Anthony
authors.initials: A
authors.lastname: Prokopowicz
authors.forename: Morgan
authors.initials: M
authors.lastname: Welzel
authors.forename: John
authors.initials: J
authors.lastname: Wolak
authors.forename: Tina
authors.initials: T
authors.lastname: Morwick
mesh_terms: D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000737:chemistry; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D010666:Phenylpropionates / Q000138:chemical synthesis / Q000737:chemistry*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C540174:3-(3-(6-(4-methyl(1,4)diazepan-1-yl)pyrazin-2-yl)phenyl)acrylic acid; D001381:Azepines; D010666:Phenylpropionates; D047390:Casein Kinase II; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim