Abstract
The cyclin-dependent kinase (CDK) inhibitor seliciclib (1, CYC202) is in phase II clinical development for the treatment of cancer. Here we describe the synthesis of novel purines with greater solubility, lower metabolic clearance, and enhanced potency versus CDKs. These compounds exhibit novel selectivity profiles versus CDK isoforms. Compound αSβR-21 inhibits CDK2/cyclin E with IC(50)=30 nM, CDK7-cyclin H with IC(50)=1.3 μM, and CDK9-cyclinT with IC(50)=0.11 μM; it (CCT68127) inhibits growth of HCT116 colon cancer cells in vitro with GI(50)=0.7 μM; and shows antitumour activity when dosed p.o. at 50mg/kg to mice bearing HCT116 solid human tumour xenografts.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Adenosine / analogs & derivatives*
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Adenosine / chemical synthesis
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Adenosine / chemistry
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Adenosine / pharmacokinetics
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Adenosine / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Female
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Humans
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology
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Purines / chemical synthesis
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Purines / chemistry*
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Purines / pharmacokinetics
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Purines / pharmacology
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Roscovitine
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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CCT68127
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Protein Kinase Inhibitors
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Purines
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Roscovitine
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Cyclin-Dependent Kinases
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Adenosine