A challenge for medicinal chemistry by the 17β-hydroxysteroid dehydrogenase superfamily: an integrated biological function and inhibition study.
A challenge for medicinal chemistry by the 17β-hydroxysteroid dehydrogenase superfamily: an integrated biological function and inhibition study.
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DOI：
10.2174/15680266113139990004
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发表时间：
2013-05
影响因子：
3.4
通讯作者：
S. Lin;D. Poirier;J. Adamski
中科院分区：
文献类型：
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作者：
S. Lin;D. Poirier;J. Adamski
17β-羟基类固醇脱氢酶（17β-HSD）超家族的成员通过同一种酶进行不同的多重催化，这显然与长期以来关于酶的高特异性的信念相矛盾。令人惊讶的是，这些多重催化可以在体外和体内协同结合，它们的功能障碍可能导致乳腺癌或前列腺癌的刺激。 17β-HSD1具有较高的雌激素激活活性，而其雄激素失活对于降低乳腺癌细胞中二氢睾酮（DHT）的周浓度具有重要意义，而DHT是细胞增殖的重要因素。 17β-HSD5 还可以在激素依赖性癌细胞中进行多种催化。除了 17β-HSD 1 和 5 之外，其他一些家族成员也具有这种双重活性，并且它们的抑制可减少激素依赖性癌症增殖。 17β-HSD1 的多特异性在结构上基于假对称雄激素，该雄激素可以通过正常和替代结合来适应狭窄的酶底物通道。非典型家族成员 17β-HSD5 拥有宽敞的结合位点，可与多种底物接触。 17β-HSD1 的表达还可以控制其他雌激素反应元件，例如 pS2，并可以调节类固醇激素受体。 17β-HSD1 在催化和基因调控中的基本参与是其与乳腺癌密切关系的基础，这归因于其漫长的进化过程。这些观察刺激了对类固醇转化酶抑制的详细研究。几十年来，设计 17β-HSD1 抑制剂最重要的工作是通过结构活性关系研究取得进展，这些研究得到小分子和蛋白质分子结构可用性的支持，并消除了抑制剂中残留的雌激素活性。现已报道第一个在体内（乳腺癌动物模型）显示出活性的 17β-HSD1 非雌激素抑制剂。
Members of the 17β-hydroxysteroid dehydrogenase (17β-HSD) superfamily perform distinct multiple catalyses by the same enzyme, apparently contradictory to the long-held beliefs regarding the high specificity of enzymes. Surprisingly, these multi-catalyses can combine synergistically in vitro and in vivo and their dysfunction may result in the stimulation of breast or prostate cancer. 17β-HSD1 possesses high estrogen activation activity, while its androgen inactivation is significant for decreasing the week concentration of dihydrotestosterone (DHT) in breast cancer cells, an important factor for cell proliferation. 17β-HSD5 can also carry out multiple catalyses in hormone-dependent cancer cells. In addition to 17β-HSDs 1 and 5 some other family members possess such dual-activity as well, and their inhibition decreases hormone- dependent cancer proliferation. The multi-specificity of 17β-HSD1 is structurally based on the pseudo-symmetric androgens that can accommodate the narrow enzyme substrate tunnel by both normal and alternative binding. The atypical family member 17β-HSD5 possesses a spacious binding site, which is accessible to several substrates. Expression of 17β- HSD1 can also control other estrogen-responsive elements such as pS2, and can regulate steroid-hormone receptors. The fundamental involvement of 17β-HSD1 in catalysis and gene regulation underlies its close relationship to breast cancer, attributable to its long evolutionary process. These observations stimulated detailed study of steroid-converting enzyme inhibition. The most significant efforts in designing 17β-HSD1 inhibitors in decades have progressed through structure activity relationship studies supported by the availability of both small and protein molecule structures, with the elimination of residual estrogenic activity in the inhibitors. The first non-estrogenic inhibitors of 17β-HSD1 to show activity in vivo (breast cancer animal model) are now reported.