Novel aromatase inhibitors by structure-guided design.
Novel aromatase inhibitors by structure-guided design.
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DOI：
10.1021/jm300930n
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发表时间：
2012-10-11
影响因子：
7.3
通讯作者：
Davies, Huw M. L.
中科院分区：
文献类型：
--
作者：
Ghosh, Debashis;Lo, Jessica;Morton, Daniel;Valette, Damien;Xi, Jingle;Griswold, Jennifer;Hubbell, Susan;Egbuta, Chinaza;Jiang, Wenhua;An, Jing;Davies, Huw M. L.
人细胞色素P450芳香酶催化雄激素合成雌激素，具有很高的特异性。芳香酶抑制剂(AIs)如依西美坦、6-亚甲基雄烯-1，4-二烯-3，17-二酮等，是治疗雌激素依赖型乳腺癌的首选药物。人胎盘芳香酶的晶体结构显示了雄激素特异的活性部位。利用结构数据设计了新型的C6取代雄烯-1，4-二烯-3，17-二酮类化合物。几个C6取代的2-烷氧基化合物抑制纯化的胎盘芳香酶，其IC50值在纳摩尔范围内。在MCF-7乳腺癌细胞系中进行的抗增殖研究表明，其中一些化合物的EC50值高于1 NM，超过了依西美坦。两种有效化合物的芳香化酶络合物的X射线结构表明，根据它们的设计，新的侧基突出到酶-底物/依西美坦络合物中未被占据的通道的开口中。X射线数据证实了所观察到的结构-活性关系。结构导向设计允许利用芳香酶特定的相互作用来开发下一代人工智能。
Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC50 values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC50 values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme–substrate/exemestane complexes. The observed structure–activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
--
作者：
Hong, Yanyan;Yu, Bin;Chen, Shiuan
通讯作者：
Chen, Shiuan
影响因子：
8
作者：
GRAHAMLORENCE, S;AMARNEH, B;SIMPSON, ER
通讯作者：
SIMPSON, ER
DOI：
10.1016/s1359-0278(97)00024-2
发表时间：
1997-01-01
期刊：
FOLDING & DESIGN
影响因子：
--
作者：
Bahar, I;Atilgan, AR;Erman, B
通讯作者：
Erman, B
影响因子：
3.4
作者：
Kittigowittana, Krisada;Yang, Chang-Tong;Bates, Roderick W.
通讯作者：
Bates, Roderick W.