Development of small-molecule cyclin D1-ablative agents

J Med Chem. 2006 Jul 27;49(15):4684-9. doi: 10.1021/jm060057h.


Previously, we demonstrated that the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist troglitazone mediated the repression of cyclin D1 in MCF-7 breast cancer cells by facilitating proteasome-facilitated proteolysis. This PPARgamma-independent mechanism provided a molecular basis for using troglitazone as scaffold to develop a novel class of cyclin D1-ablative agents. The proof of principle of this premise is provided by Delta2TG, in which the introduction of a double bond adjacent to the thiazolidinedione ring abrogated the PPARgamma activity while retaining the activity in cyclin D1 repression. Structural optimization of Delta2TG led to STG28 [(S)-5-(4-{[6-(allyloxy)-2,5,7,8-tetramethylchroman-2-yl]methoxy}-3-methoxybenzylidene)thiazolidine-2,4-dione], which exhibited low micromolar potency in ablating cyclin D1 and inhibiting MCF-7 cell proliferation. It is noteworthy that STG28 mediated the proteasomal degradation of cyclin D1 with a high degree of specificity. Exposure to STG28 did not cause any appreciable change in the expression levels of a series of other cyclins and CDK-dependent kinases. In light of the pivotal role of cyclin D1 in promoting tumorigenesis and drug resistance, this novel cyclin D1-ablating agent may have therapeutic relevance in cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromans / chemical synthesis*
  • Chromans / chemistry
  • Chromans / pharmacology
  • Cyclin D1 / metabolism*
  • Humans
  • Hydrolysis
  • Molecular Conformation
  • PPAR gamma / agonists
  • Proteasome Endopeptidase Complex / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiazolidinediones / chemical synthesis*
  • Thiazolidinediones / chemistry
  • Thiazolidinediones / pharmacology
  • Troglitazone


  • 5-(4-((6-(allyloxy)-2,5,7,8-tetramethylchroman-2-yl)methoxy)-3-methoxybenzylidene)thiazolidine-2,4-dione
  • Antineoplastic Agents
  • Benzopyrans
  • Chromans
  • PPAR gamma
  • Thiazolidinediones
  • Cyclin D1
  • Proteasome Endopeptidase Complex
  • Troglitazone