Paterni Ilaria, Bertini Simone, Granchi Carlotta, Tuccinardi Tiziano, Macchia Marco, Martinelli Adriano, Caligiuri Isabella, Toffoli Giuseppe, Rizzolio Flavio, Carlson Kathryn E, Katzenellenbogen Benita S, Katzenellenbogen John A, Minutolo Filippo
Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy.
J Med Chem. 2015 Feb 12;58(3):1184-94. doi: 10.1021/jm501829f. Epub 2015 Jan 14.
Estrogen receptor β (ERβ) selective agonists are considered potential therapeutic agents for a variety of pathological conditions, including several types of cancer. Their development is particularly challenging, since differences in the ligand binding cavities of the two ER subtypes α and β are minimal. We have carried out a rational design of new salicylketoxime derivatives which display unprecedentedly high levels of ERβ selectivity for this class of compounds, both in binding affinity and in cell-based functional assays. An endogenous gene expression assay was used to further characterize the pharmacological action of these compounds. Finally, these ERβ-selective agonists were found to inhibit proliferation of a glioma cell line in vitro. Most importantly, one of these compounds also proved to be active in an in vivo xenograft model of human glioma, thus demonstrating the high potential of this type of compounds against this devastating disease.
雌激素受体β(ERβ)选择性激动剂被认为是针对多种病理状况(包括几种类型的癌症)的潜在治疗药物。它们的研发极具挑战性,因为两种雌激素受体亚型α和β的配体结合腔差异极小。我们对新型水杨基酮肟衍生物进行了合理设计,这类化合物在结合亲和力和基于细胞的功能测定中,均展现出了前所未有的高ERβ选择性水平。我们使用内源性基因表达测定法进一步表征了这些化合物的药理作用。最后,发现这些ERβ选择性激动剂在体外可抑制胶质瘤细胞系的增殖。最重要的是,其中一种化合物在人胶质瘤的体内异种移植模型中也被证明具有活性,从而证明了这类化合物对抗这种毁灭性疾病的巨大潜力。