Huang J.-W.Shiau C.-W.Yang J.Wang D.-S.HAO-CHIEH CHIUChen C.-Y.Chen C.-S.2021-06-242021-06-2420060022-2623https://scholars.lib.ntu.edu.tw/handle/123456789/566138Previously, we demonstrated that the peroxisome proliferator-activated receptor γ (PPARγ) agonist troglitazone mediated the repression of cyclin D1 in MCF-7 breast cancer cells by facilitating proteasome-facilitated proteolysis. This PPARγ-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 Δ2TG, in which the introduction of a double bond adjacent to the thiazolidinedione ring abrogated the PPARγ activity while retaining the activity in cyclin D1 repression. Structural optimization of Δ2TG 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. ? 2006 American Chemical Society.[SDGs]SDG32,4 thiazolidinedione derivative; 5 [4 [(6 allyloxy 2,5,7,8 tetramethylchroman 2 yl)methoxy] 3 methoxybenzylidene]thiazolidine 2,4 dione; antineoplastic agent; beta actin; cyclin D1; cyclin dependent kinase; peroxisome proliferator activated receptor gamma; peroxisome proliferator activated receptor gamma agonist; proteasome; stg 28; troglitazone; unclassified drug; article; cancer resistance; carcinogenesis; cell proliferation; cell strain MCF 7; chemical bond; controlled study; drug mechanism; drug potency; drug protein binding; human; human cell; polymerase chain reaction; protein degradation; stereospecificity; structure activity relation; Antineoplastic Agents; Benzopyrans; Cell Line, Tumor; Cell Proliferation; Chromans; Cyclin D1; Humans; Hydrolysis; Molecular Conformation; PPAR gamma; Proteasome Endopeptidase Complex; Stereoisomerism; Structure-Activity Relationship; Thiazolidinedionesjournal article10.1021/jm060057h168540742-s2.0-33746746418