A new series of potent oxindole inhibitors of CDK2.
A novel series of oxindole-type inhibitors of CDK2 that have heteroatom substituted alkynyl moieties at their C-4 position is described. These novel 4-alkynyl-substituted inhibitors have superior potency relative to their parent compound in free enzyme and in cell based assays. The crystal structure of CDK2 in complex with one of these analogues was determined and gives insight to their increased potency. The biochemical evaluation of a representative derivative is also described.
Luk
Kin-Chun
KC
Hoffmann-La Roche Inc., 340 Kingsland St., Nutley, NJ 07110-1199, USA.
Simcox
Mary Ellen
ME
Schutt
Andy
A
Rowan
Karen
K
Thompson
Thelma
T
Chen
Yi
Y
Kammlott
Ursula
U
DePinto
Wanda
W
Dunten
Pete
P
Dermatakis
Apos
A
D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2; D004247:DNA / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D017239:Paclitaxel / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007211:Indoles; D004247:DNA; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D017239:Paclitaxel