Development of small-molecule cyclin D1-ablative agents.

Abstract

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.

• Authors: Jui-Wen Huang, Chung-Wai Shiau, Jian Yang, Da-Sheng Wang, Hao-Chieh Chiu, Ching-Yu Chen, Ching-Shih Chen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 15 Pg. 4684-9 (Jul 27 2006) ISSN: 0022-2623 [Print] United States
• PMID: 16854074 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

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