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.
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.
Qian
Kevin
K
Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut 06801-0368, USA.
Wang
Lian
L
Cywin
Charles L
CL
Farmer
Bennett T
BT
Hickey
Eugene
E
Homon
Carol
C
Jakes
Scott
S
Kashem
Mohammed A
MA
Lee
George
G
Leonard
Scott
S
Li
Jun
J
Magboo
Ronald
R
Mao
Wang
W
Pack
Edward
E
Peng
Charlene
C
Prokopowicz
Anthony
A
Welzel
Morgan
M
Wolak
John
J
Morwick
Tina
T
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
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