4-(Phenylaminomethylene)isoquinoline-1,3(2 H ,4 H )-diones as Potent and Selective Inhibitors of the Cyclin-Dependent Kinase 4 (CDK4)

Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 07/2008; 51(12):3507-25. DOI: 10.1021/jm800072z
Source: PubMed


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.

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