A novel gene expression analytics-based approach to structure aided design of rexinoids for development as next-generation cancer therapeutics.
A novel gene expression analytics-based approach to structure aided design of rexinoids for development as next-generation cancer therapeutics.
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DOI：
10.1016/j.steroids.2018.04.009
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发表时间：
2018-07
期刊：
影响因子：
2.7
通讯作者：
Marshall PA
中科院分区：
文献类型：
--
作者：
Hanish BJ;Hackney Price JF;Kaneko I;Ma N;van der Vaart A;Wagner CE;Jurutka PW;Marshall PA
Rexinoid是一种强大的配体，可以与维甲酸X受体(RXRs)结合，在治疗包括癌症在内的多种疾病方面显示出巨大的前景。然而，只有一种雷克沙星，贝克沙罗汀(Targretin TM)成功地从试验台过渡到临床并用于治疗皮肤T细胞淋巴瘤(CTCL)。我们的目标是开发比贝沙罗汀副作用小的新型强效类维A酸类药物。为此，我们合成了一系列具有EC50值和类似贝沙罗汀生物活性的Rexinoid。为了确定它们是否适合进一步的下游分析，并确定潜在的候选类似物用于临床翻译，我们在培养中处理人CTCL细胞，并使用微阵列技术来评估基因表达谱。我们分析了12个Rexinoid，发现它们可以根据基因表达分为三个不同的类别：类似于贝沙罗汀，与贝沙罗汀略有不同，与贝沙罗汀有很大不同。令人惊讶的是，贝沙罗汀母体化合物结构的微小变化导致了基因表达谱的显著差异。此外，在预期对治疗前景很重要的基因的表达上，特定的类似物明显偏离了我们的假设。然而，对其表达进行分析的基因的启动子分析表明，沿着结构框架的一般调控趋势。我们的结果表明，某些结构基序，特别是在类似物4和类似物9中发现的基本框架，是为未来的研究和治疗应用生成额外的rexinoid的重要起点。
Rexinoids are powerful ligands that bind to retinoid-X-receptors (RXRs) and show great promise as therapeutics for a wide range of diseases, including cancer. However, only one rexinoid, bexarotene (Targretin TM) has been successfully transitioned from the bench to the clinic and used to treat cutaneous T-cell lymphoma (CTCL). Our goal is to develop novel potent rexinoids with a less untoward side effect profile than bexarotene. To this end, we have synthesized a wide array of rexinoids with EC50 values and biological activity similar to bexarotene. In order to determine their suitability for additional downstream analysis, and to identify potential candidate analogs for clinical translation, we treated human CTCL cells in culture and employed microarray technology to assess gene expression profiles. We analyzed twelve rexinoids and found they could be stratified into three distinct categories based on their gene expression: similar to bexarotene, moderately different from bexarotene, and substantially different from bexarotene. Surprisingly, small changes in the structure of the bexarotene parent compound led to marked differences in gene expression profiles. Furthermore, specific analogs diverged markedly from our hypothesis in expression of genes expected to be important for therapeutic promise. However, promoter analysis of genes whose expression was analyzed indicates general regulatory trends along structural frameworks. Our results suggest that certain structural motifs, particularly the basic frameworks found in analog 4 and analog 9, represent important starting points to exploit in generating additional rexinoids for future study and therapeutic applications.
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影响因子：
14.9
作者：
Babicki S;Arndt D;Marcu A;Liang Y;Grant JR;Maciejewski A;Wishart DS
通讯作者：
Wishart DS
影响因子：
3.4
作者：
Chen XQ;Yang S;Li ZY;Lu HS;Kang MQ;Lin TY
通讯作者：
Lin TY
影响因子：
7.3
作者：
Jurutka, Peter W.;Kaneko, Ichiro;Wagner, Carl E.
通讯作者：
Wagner, Carl E.
类维生素X受体及其配体。
DOI：
10.1016/j.bbalip.2011.09.014
发表时间：
2012-01
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Dawson MI;Xia Z
通讯作者：
Xia Z
影响因子：
14.9
作者：
Huang, Da Wei;Sherman, Brad T.;Lempicki, Richard A.
通讯作者：
Lempicki, Richard A.