Development of thioquinazolinones, allosteric Chk1 kinase inhibitors.
A high throughput screening campaign was designed to identify allosteric inhibitors of Chk1 kinase by testing compounds at high concentration. Activity was then observed at K(m) for ATP and at near-physiological concentrations of ATP. This strategy led to the discovery of a non-ATP competitive thioquinazolinone series which was optimized for potency and stability. An X-ray crystal structure for the complex of our best inhibitor bound to Chk1 was solved, indicating that it binds to an allosteric site approximately 13A from the ATP binding site. Preliminary data is presented for several of these compounds.
Converso
Antonella
A
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486, USA. antonella_converso@merck.com
Hartingh
Timothy
T
Garbaccio
Robert M
RM
Tasber
Edward
E
Rickert
Keith
K
Fraley
Mark E
ME
Yan
Youwei
Y
Kreatsoulas
Constantine
C
Stirdivant
Steve
S
Drakas
Bob
B
Walsh
Eileen S
ES
Hamilton
Kelly
K
Buser
Carolyn A
CA
Mao
Xianzhi
X
Abrams
Marc T
MT
Beck
Stephen C
SC
Tao
Weikang
W
Lobell
Rob
R
Sepp-Lorenzino
Laura
L
Zugay-Murphy
Joan
J
Sardana
Vinod
V
Munshi
Sanjeev K
SK
Jezequel-Sur
Sylvie Marie
SM
Zuck
Paul D
PD
Hartman
George D
GD
D001665:Binding Sites; D000071877:Checkpoint Kinase 1; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1