title: 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.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, 336 Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA.
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Da-Sheng
authors.initials: DS
authors.lastname: Wang
authors.forename: Hao-Chieh
authors.initials: HC
authors.lastname: Chiu
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Chen
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008968:Molecular Conformation; D047495:PPAR gamma / Q000819:agonists; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077288:Troglitazone
chemical_list: C513003:5-(4-((6-(allyloxy)-2,5,7,8-tetramethylchroman-2-yl)methoxy)-3-methoxybenzylidene)thiazolidine-2,4-dione; D000970:Antineoplastic Agents; D001578:Benzopyrans; D002839:Chromans; D047495:PPAR gamma; D045162:Thiazolidinediones; D019938:Cyclin D1; D046988:Proteasome Endopeptidase Complex; D000077288:Troglitazone