Mechanism of androgen receptor antagonism by bicalutamide in the treatment of prostate cancer.
Mechanism of androgen receptor antagonism by bicalutamide in the treatment of prostate cancer.
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DOI：
10.1021/bi102059z
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发表时间：
2011-05-17
期刊：
影响因子：
2.9
通讯作者：
Hagler AT
中科院分区：
文献类型：
--
作者：
Osguthorpe DJ;Hagler AT
雄激素受体（AR）在调节包括前列腺在内的多种组织中的基因表达中起关键作用。在后一种作用中，它是开发用于治疗前列腺癌的新化疗药物的主要靶标之一，也是目前最广泛处方的用于这种疾病的药物比卡鲁胺（Bcu）的靶标。鉴于其重要性，以及任何拮抗剂-AR复合物的晶体结构的缺乏，我们已经进行了一系列基于AR-Bcu复合物的分子动力学模拟和Bcu的量子力学（QM）计算，以阐明该关键靶标拮抗作用的结构基础。出现的结构表明，比卡鲁胺通过进入邻近激素结合位点（HBS）的额外结合口袋（B位点）拮抗AR，该结合口袋由置换螺旋12诱导。这扭曲了辅激活因子结合位点，导致转录失活。发现比卡鲁胺的另一种等能构象状态结合在膨胀的激素口袋中，而不会实质性地干扰螺旋12或共激活剂结合位点。因此，根据这些结构，比卡鲁胺在不同环境中表现出的拮抗作用的结构基础和激动剂特性的潜在机制可能是合理的。此外，拮抗剂结构，特别是诱导的第二位点（B-位点）为设计新的抗雄激素提供了结构框架。
The androgen receptor (AR) plays a key role in a regulating gene expression in a variety of tissues, including the prostate. In the latter role it is one of the primary targets in the development of new chemotherapeutics for treatment of prostate cancer, as well as being the target of the most widely prescribed current drug, bicalutamide (Bcu), for this disease. In view of it’s importance, and the absence of a crystal structure for any antagonist-AR complex, we have carried out a series of molecular dynamics based simulations of the AR-Bcu complex and quantum mechanical (QM) calculations of Bcu, to elucidate the structural basis for antagonism of this key target. The structures which emerge show that bicalutamide antagonizes AR by accessing an additional binding pocket (B-site) adjacent to the hormone binding site (HBS), induced by displacing helix 12. This distorts the coactivator binding site and results in the inactivation of transcription. An alternative equienergetic conformational state of bicalutamide was found to bind in an expanded hormone pocket without materially perturbing either helix 12 or the coactivator binding site. Thus both the structural basis of antagonism and the mechanism underlying agonist properties displayed by bicalutamide in different environments may be rationalized in terms of these structures. In addition the antagonist structure and especially the induced second site (B-site) provides a structural framework for the design of novel antiandrogens.
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影响因子：
168.9
作者：
Scher, Howard I.;Beer, Tomasz M.;Higano, Celestia S.;Anand, Aseem;Taplin, Mary-Ellen;Efstathiou, Eleni;Rathkopf, Dana;Shelkey, Julia;Yu, Evan Y.;Alumkal, Joshi;Hung, David;Hirmand, Mohammad;Seely, Lynn;Morris, Michael J.;Danila, Daniel C.;Humm, John;Larson, Steve;Fleisher, Martin;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
影响因子：
82.9
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Sawyers, CL
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4.8
作者：
Bohl, CE;Miller, DD;Dalton, JT
通讯作者：
Dalton, JT
影响因子：
56.9
作者：
HUGGINS, C
通讯作者：
HUGGINS, C
影响因子：
4.8
作者：
Matias, PM;Donner, P;Carrondo, MA
通讯作者：
Carrondo, MA