Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase.
From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1.
Garbaccio
Robert M
RM
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. robert_garbaccio@merck.com
Huang
Shaei
S
Tasber
Edward S
ES
Fraley
Mark E
ME
Yan
Youwei
Y
Munshi
Sanjeev
S
Ikuta
Mari
M
Kuo
Lawrence
L
Kreatsoulas
Constanine
C
Stirdivant
Steve
S
Drakas
Bob
B
Rickert
Keith
K
Walsh
Eileen S
ES
Hamilton
Kelly A
KA
Buser
Carolyn A
CA
Hardwick
James
J
Mao
Xianzhi
X
Beck
Stephen C
SC
Abrams
Marc T
MT
Tao
Weikang
W
Lobell
Rob
R
Sepp-Lorenzino
Laura
L
Hartman
George D
GD
D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010777:Photochemistry; D011494:Protein Kinases / Q000737:chemistry / Q000187:drug effects*; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D015363:Quinolones; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1