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Design, synthesis and biological evaluation of 6-pyridylmethylaminopurines as CDK inhibitors.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2011 Nov 15; Vol. 19 (22), pp. 6949-65. Date of Electronic Publication: 2011 Aug 31. - Publication Year :
- 2011
-
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.<br /> (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Subjects :
- Adenosine chemical synthesis
Adenosine chemistry
Adenosine pharmacokinetics
Adenosine pharmacology
Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents pharmacology
Female
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors pharmacokinetics
Protein Kinase Inhibitors pharmacology
Purines chemical synthesis
Purines pharmacokinetics
Purines pharmacology
Roscovitine
Xenograft Model Antitumor Assays
Adenosine analogs & derivatives
Cyclin-Dependent Kinases antagonists & inhibitors
Protein Kinase Inhibitors chemistry
Purines chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 19
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21982796
- Full Text :
- https://doi.org/10.1016/j.bmc.2011.08.051