Benzothiophenone Derivatives Targeting Mutant Forms of Estrogen Receptor-α in Hormone-Resistant Breast Cancers
Benzothiophenone Derivatives Targeting Mutant Forms of Estrogen Receptor-α in Hormone-Resistant Breast Cancers
复制标题
苯并噻吩酮衍生物靶向激素抗性乳腺癌中雌激素受体-α 的突变形式
DOI：
--
复制
发表时间：
2018
影响因子：
5.6
通讯作者：
P. Rennie
中科院分区：
文献类型：
--
作者：
Kriti Singh;R. Munuganti;N. Lallous;Kush Dalal;J. Yoon;Aishwariya Sharma;Takeshi Yamazaki;A. Cherkasov;P. Rennie
雌激素受体α阳性(ERα+)乳腺癌占所有浸润性乳腺癌病例的75%，而对ER导向治疗的新发或获得性耐药也在增加。导致这种现象的因素很多，包括最近报道的ESR1基因突变，如Y537S，它放大了协同激活子与ERα的相互作用，促进了ERα功能的结构性激活。在此，我们认为，直接靶向ERα上的激活功能-2(AF2)位点是克服乳腺癌突变驱动耐药的一种有前途的替代治疗策略。采用系统的计算机引导的药物发现方法开发了一种有效的ERα抑制剂，并通过一系列实验对其进行了广泛的评估，以确认其AF2的特异性活性。我们证明，开发的小分子抑制剂有效地阻止了ERα与辅活化子的相互作用，对他莫昔芬耐药细胞表现出强大的抗增殖作用，并下调了ERα依赖的基因，有效地减少了受体与染色质的结合。值得注意的是，所鉴定的先导化合物成功地抑制了临床上观察到的已知的结构性活性、耐药相关的ERα突变形式。总之，这项研究报告了一类新型ERαAF2抑制剂的开发，这种抑制剂有可能通过一种独特的机制有效地抑制ERα活性，并绕过乳腺癌中突变驱动的耐药问题。
Estrogen receptor-α positive (ERα+) breast cancers represent 75% of all invasive breast cancer cases, while de novo or acquired resistance to ER-directed therapy is also on the rise. Numerous factors contribute to this phenomenon including the recently-reported ESR1 gene mutations such as Y537S, which amplifies co-activator interactions with ERα and promotes constitutive activation of ERα function. Herein, we propose that direct targeting of the activation function-2 (AF2) site on ERα represents a promising alternative therapeutic strategy to overcome mutation-driven resistance in breast cancer. A systematic computer-guided drug discovery approach was employed to develop a potent ERα inhibitor that was extensively evaluated by a series of experiments to confirm its AF2-specific activity. We demonstrate that the developed small-molecule inhibitor effectively prevents ERα-coactivator interactions and exhibits a strong anti-proliferative effect against tamoxifen-resistant cells, as well as downregulates ERα-dependent genes and effectively diminishes the receptor binding to chromatin. Notably, the identified lead compound successfully inhibits known constitutively-active, resistance-associated mutant forms of ERα observed in clinical settings. Overall, this study reports the development of a novel class of ERα AF2 inhibitors, which have the potential to effectively inhibit ERα activity by a unique mechanism and to circumvent the issue of mutation-driven resistance in breast cancer.
登录
查看更多内容
影响因子：
7.3
作者：
Halgren, TA;Murphy, RB;Banks, JL
通讯作者：
Banks, JL
影响因子：
4
作者：
Gunther, Jillian R.;Moore, Terry W.;Katzenettenbogen, John A.
通讯作者：
Katzenettenbogen, John A.
影响因子：
4.8
作者：
Duplessis, Tamika T.;Williams, Christopher C.;Rowan, Brian G.
通讯作者：
Rowan, Brian G.
DOI：
10.1073/pnas.0510596103
发表时间：
2006-06-27
影响因子：
11.1
作者：
Wang, Yong;Chirgadze, Nickolay Y.;Burris, Thomas P.
通讯作者：
Burris, Thomas P.
影响因子：
7.3
作者：
Friesner, RA;Banks, JL;Shenkin, PS
通讯作者：
Shenkin, PS