Selectively targeting prostate cancer with antiandrogen equipped histone deacetylase inhibitors.
Selectively targeting prostate cancer with antiandrogen equipped histone deacetylase inhibitors.
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DOI：
10.1021/cb400542w
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发表时间：
2013-11-15
影响因子：
4
通讯作者：
Oyelere AK
中科院分区：
文献类型：
--
作者：
Gryder BE;Akbashev MJ;Rood MK;Raftery ED;Meyers WM;Dillard P;Khan S;Oyelere AK
与癌症进展相关的多种细胞过程受蛋白质的乙酰化状态调节。在这些过程中，通过组蛋白蛋白质进行染色质重塑，由相反的组蛋白脱乙酰酶（HDAC）和组蛋白乙酰转移酶（HAT）酶控制。组蛋白去乙酰化酶抑制剂（HDACi）在临床前癌症模型中显示出巨大的前景，但治疗实体瘤的临床试验未能改善患者的生存率。这部分是由于HDACi不能有效地在癌细胞中积累。为了解决这个问题，我们设计了具有次级药效团的HDACi，以促进在恶性细胞中的选择性积累。我们提出的第一个例子HDACi化合物靶向前列腺肿瘤装备他们的额外能力，结合雄激素受体（AR）与非甾体抗雄激素部分。这些新的双作用分子中的先导物与AR结合，并在比临床抗雄激素更低的浓度下停止AR转录活性。它们以低纳摩尔效力抑制HDAC的关键亚型。荧光显微镜显示不同程度的AR核定位在响应这些化合物，与它们的HDAC活性相关。这些生物学特性转化为对激素依赖性（AR+）LNCaP的有效抗癌活性，并在较小程度上对激素非依赖性（AR-）DU 145前列腺癌具有抗癌活性，同时大大降低了对非癌细胞的毒性。这表明，用单个化学探针接合多个生物靶标可以实现有效的细胞类型选择性反应。
Diverse cellular processes relevant to cancer progression are regulated by the acetylation status of proteins. Among such processes is chromatin remodeling via histone proteins, controlled by opposing histone deacetylase (HDAC) and histone acetyltransferase (HAT) enzymes. Histone deacetylase inhibitors (HDACi) show great promise in preclinical cancer models, but clinical trials treating solid tumors have failed to improve patient survival. This is due in part to an inability of HDACi to effectively accumulate in cancerous cells. To address this problem we designed HDACi with secondary pharmacophores to facilitate selective accumulation in malignant cells. We present the first example of HDACi compounds targeted to prostate tumors by equipping them with the additional ability to bind the androgen receptor (AR) with non-steroidal antiandrogen moieties. Leads among these new dual-acting molecules bind to the AR and halt AR transcriptional activity at lower concentrations than clinical antiandrogens. They inhibit key isoforms of HDAC with low nanomolar potency. Fluorescent microscopy reveals varying degrees of AR nuclear localization in response to these compounds that correlates with their HDAC activity. These biological properties translate into potent anticancer activity against hormone dependent (AR+) LNCaP and to a lesser extent against hormone independent (AR−) DU145 prostate cancer, while having greatly reduced toxicity in non-cancerous cells. This illustrates that engaging multiple biological targets with a single chemical probe can achieve both potent and cell-type selective responses.
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影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
影响因子：
7.3
作者：
Cogan, PS;Koch, TH
通讯作者：
Koch, TH
影响因子：
15
作者：
Himo, F;Lovell, T;Fokin, VV
通讯作者：
Fokin, VV
影响因子：
7.3
作者：
Jung ME;Ouk S;Yoo D;Sawyers CL;Chen C;Tran C;Wongvipat J
通讯作者：
Wongvipat J