| Autor: |
Tsou HR; Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, USA. tsouh@wyeth.com, Otteng M, Tran T, Floyd MB Jr, Reich M, Birnberg G, Kutterer K, Ayral-Kaloustian S, Ravi M, Nilakantan R, Grillo M, McGinnis JP, Rabindran SK |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2008 Jun 26; Vol. 51 (12), pp. 3507-25. |
| DOI: |
10.1021/jm800072z |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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