4-(Phenylaminomethylene)isoquinoline-1,3(2H,4H)-diones as Potent and Selective Inhibitors of the Cyclin-Dependent Kinase 4 (CDK4)
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- 作者：Hwei-Ru Tsou ; Mercy Otteng ; Tritin Tran ; M. Brawner Floyd Jr. ; Marvin Reich ; Gary Birnberg ; Kristina Kutterer ; Semiramis Ayral-Kaloustian ; Malini Ravi ; Ramaswamy Nilakantan ; Mary Grillo ; John P. McGin
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：June 26, 2008
- 年：2008
- 卷：51
- 期：12
- 页码：3507 - 3525
- 全文大小：747K
- 年卷期：v.51,no.12(June 26, 2008)
- ISSN：1520-4804
文摘
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 substitutent 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.