Exploring the structural requirements for inhibition of the ubiquitin E3 ligase breast cancer associated protein 2 (BCA2) as a treatment for breast cancer.
Exploring the structural requirements for inhibition of the ubiquitin E3 ligase breast cancer associated protein 2 (BCA2) as a treatment for breast cancer.
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DOI：
10.1021/jm901757t
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发表时间：
2010-04-08
影响因子：
7.3
通讯作者：
Westwell AD
中科院分区：
文献类型：
--
作者：
Brahemi G;Kona FR;Fiasella A;Buac D;Soukupová J;Brancale A;Burger AM;Westwell AD
锌排出醛脱氢酶（ALDH）抑制药物双硫仑（DSF）被发现是一种具有强效抗肿瘤活性的乳腺癌相关蛋白2（BCA 2）抑制剂。本文描述了我们在合成和评价新系列的锌亲和分子以探索选择性BCA 2抑制性抗肿瘤活性的结构要求方面的工作。基于在表达BCA 2的乳腺癌细胞系中和针对重组BCA 2蛋白的选择性活性，发现需要N（C=S）S-S基序。值得注意的是，发现DSF类似物（3a和3c）和二硫代（过氧）硫代酸酯化合物（5d和5 f）在BCA 2阳性MCF-7和T47 D细胞中具有有效活性（亚微摩尔IC 50），但在BCA 2阴性MDA-MB-231乳腺癌细胞和正常乳腺上皮细胞系MCF 10A中无活性（IC 50>10 μM）。在同基因BCA 2 +ve MDA-MB-231/ER细胞系中的测试恢复了在BCA 2阴性MDA-MB-231细胞系中无活性的化合物的抗肿瘤活性。相比之下，结构相关的二硫代氨基甲酸酯和苯并异噻唑酮（缺乏二硫键）均无活性。另外发现化合物5d和5 f缺乏ALDH抑制活性，提示选择性E3连接酶抑制活性，值得进一步开发。
The zinc-ejecting aldehyde dehydrogenase (ALDH) inhibitory drug disulfiram (DSF) was found to be a breast cancer-associated protein 2 (BCA2) inhibitor with potent antitumor activity. We herein describe our work in the synthesis and evaluation of new series of zinc-affinic molecules to explore the structural requirements for selective BCA2-inhibitory antitumor activity. An N(C=S)S-S motif was found to be required, based on selective activity in BCA2-expressing breast cancer cell lines and against recombinant BCA2 protein. Notably, the DSF analogs (3a and 3c) and dithio(peroxo)thioate compounds (5d and 5f) were found to have potent activity (submicromolar IC50) in BCA2 positive MCF-7 and T47D cells but were inactive (IC50 >10 μM) in BCA2 negative MDA-MB-231 breast cancer cells and the normal breast epithelial cell line MCF10A. Testing in the isogenic BCA2 +ve MDA-MB-231/ER cell line restored antitumor activity for compounds that were inactive in the BCA2 negative MDA-MB-231 cell line. In contrast, structurally related dithiocarbamates and benzisothiazolones (lacking the disulfide bond) were all inactive. Compounds 5d and 5f were additionally found to lack ALDH-inhibitory activity, suggestive of selective E3 ligase-inhibitory activity and worthy of further development.
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影响因子：
5.2
作者：
Azizi, Najmedin;Aryanasab, Fezzeh;Saidi, Mohammad R.
通讯作者：
Saidi, Mohammad R.
影响因子：
2.4
作者：
Adams, J;Kauffman, M
通讯作者：
Kauffman, M
DOI：
10.1021/je60040a040
发表时间：
1969-01-01
期刊：
JOURNAL OF CHEMICAL AND ENGINEERING DATA
影响因子：
--
作者：
GILMORE, WF;CLARK, RN
通讯作者：
CLARK, RN
影响因子：
5.2
作者：
Correa, Arkaitz;Tellitu, Imanol;SanMartin, Raul
通讯作者：
SanMartin, Raul
影响因子：
1.8
作者：
Ali, MH;McDermott, M
通讯作者：
McDermott, M