A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo

Oncogene. 2007 Mar 22;26(13):1829-39. doi: 10.1038/sj.onc.1209987. Epub 2006 Oct 16.

Abstract

One strategy in the development of anticancer therapeutics has been to arrest malignant proliferation through inhibition of the enzymatic activity of cyclin-dependent kinases (cdks), which are key regulatory molecules of the cell cycle. Over the past few years, numerous compounds with remarkable cdk inhibitory activity have been studied in cancer therapy, although it is very difficult to point out the best cdk to target. An excellent candidate appears to be cdk2, whose alteration is a pathogenic hallmark of tumorigenesis. The small molecule described in our study showed an inhibitory effect on the kinase activity of cdk2, a significant growth arrest observed in a colony formation assay and a reduction in the size of the tumor in nude mice, thus suggesting its potential role as a promising new type of mechanism-based antitumor drug, also for the treatment of hyperproliferative disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Cell Cycle*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Mice
  • Molecular Sequence Data
  • Neoplasms, Experimental / pathology*
  • Peptides / pharmacology*
  • Retinoblastoma-Like Protein p130 / chemistry
  • Retinoblastoma-Like Protein p130 / physiology*

Substances

  • Peptides
  • Rbl2 protein, mouse
  • Retinoblastoma-Like Protein p130
  • Cyclin-Dependent Kinase 2