4-(Phenylaminomethylene)isoquinoline-1,3(2H,4H)-diones as potent and selective inhibitors of the cyclin-dependent kinase 4 (CDK4).
The cyclin-dependent kinases (CDKs), as complexes with their respective partners, the cyclins, are critical regulators of cell cycle progression. Because aberrant regulations of CDK4/cyclin D1 lead to uncontrolled cell proliferation, a hallmark of cancer, small-molecule inhibitors of CDK4/cyclin D1 are attractive as prospective antitumor agents. The series of 4-(phenylaminomethylene)isoquinoline-1,3(2H,4H)-dione derivatives reported here represents a novel class of potent inhibitors that selectively inhibit CDK4 over CDK2 and CDK1 activities. In the headpiece of the 4-(phenylaminomethylene)isoquinoline-1,3(2H,4H)-dione, a basic amine substituent is required on the aniline ring for the CDK4 inhibitory activity. The inhibitory activity is further enhanced when an aryl or heteroaryl substituent is introduced at the C-6 position of the isoquinoline-1,3(2H,4H)-dione core. We present here SAR data and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors.
Tsou
Hwei-Ru
HR
Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, USA. tsouh@wyeth.com
Otteng
Mercy
M
Tran
Tritin
T
Floyd
M Brawner
MB
Reich
Marvin
M
Birnberg
Gary
G
Kutterer
Kristina
K
Ayral-Kaloustian
Semiramis
S
Ravi
Malini
M
Nilakantan
Ramaswamy
R
Grillo
Mary
M
McGinnis
John P
JP
Rabindran
Sridhar K
SK
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007546:Isoquinolines; D016160:Retinoblastoma Protein; D051358:Cyclin-Dependent Kinase 4