Novel pyrrolyllactone and pyrrolyllactam indolinones as potent cyclin-dependent kinase 2 inhibitors.
Cyclin-dependent kinases (CDKs) are essential in the control of cell cycle progression. Inhibition of CDKs represents a new approach for pharmacological intervention in the treatment of a variety of proliferative diseases, especially cancer. Based on the crystal structure of CDK2 in complex with an imidazole indolinone compound 1 (SU9516), lead optimization through modeling, synthesis, and SAR studies has led to the discovery of a novel series of pyrrolyllactone and pyrrolyllactam indolinones as potent CDK2 inhibitors.
SUGEN, Inc., 230 East Grand Ave., South San Francisco, CA 94080, USA. sharon-li@sugen.com
Xiaoyuan
X
Li
Ping
P
Huang
Jingrong Jean
JJ
Cui
Jennifer
J
Zhang
Cho
C
Tang
D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors*; D051357:Cyclin-Dependent Kinase 2; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000737:chemistry* / Q000494:pharmacology; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D007769:Lactams; D007783:Lactones; C029899:imidazole; D000255:Adenosine Triphosphate; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2