Selected approaches for rational drug design and high throughput screening to identify anti-cancer molecules.
Selected approaches for rational drug design and high throughput screening to identify anti-cancer molecules.
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DOI：
10.2174/187152012803529709
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发表时间：
2012-11
影响因子：
2.8
通讯作者：
Fisher PB
中科院分区：
文献类型：
--
作者：
Hedvat M;Emdad L;Das SK;Kim K;Dasgupta S;Thomas S;Hu B;Zhu S;Dash R;Quinn BA;Oyesanya RA;Kegelman TP;Sokhi UK;Sarkar S;Erdogan E;Menezes ME;Bhoopathi P;Wang XY;Pomper MG;Wei J;Wu B;Stebbins JL;Diaz PW;Reed JC;Pellecchia M;Sarkar D;Fisher PB
基于结构的建模结合合理的药物设计和高通量筛选方法为鉴定和开发具有治疗潜力的先导化合物提供了巨大的潜力。本综述的重点是这两种方法使用明确的例子的基础上产生的棉酚通过合理的设计和应用程序的癌症特异性启动子来自进展升高基因-3的特定衍生物。棉酚衍生物Sabutoclax（BI-97C1）对多种人类肿瘤表现出有效的抗肿瘤活性。棉酚与Bcl-XL结合的对接结构模型提供了一个虚拟的结构-活性-关系，其中在合理的基础上预测适当的修饰。这些基于结构的研究导致Sabutoclax的分离，Sabutoclax是Apogossypol的光学纯异构体，显示出上级功效和降低的毒性。这些研究说明了基于结构的建模与合理设计相结合的力量，以预测适当的衍生物的先导化合物进行经验测试和生物活性评价。癌症药物发现的另一种方法利用癌症特异性启动子作为转化状态的读出。Progression Elevated Gene-3的启动子区就是这样一种具有癌症特异性活性的启动子。该启动子的特异性已被开发作为构建选择性杀死癌细胞的癌症终止子病毒的手段，以及作为特异性可视化体内癌症生长而没有正常组织背景的系统成像模式。筛选抑制进展升高基因-3启动子的小分子抑制剂可以为癌症治疗提供相关的先导化合物，其可以与进一步的基于结构的方法组合，从而开发用于癌症治疗的新型化合物。
Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specific-promoter derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI-97C1) displays potent anti-tumor activity against a diverse spectrum of human tumors. The model of the docked structure of Gossypol bound to Bcl-XL provided a virtual structure-activity-relationship where appropriate modifications were predicted on a rational basis. These structure-based studies led to the isolation of Sabutoclax, an optically pure isomer of Apogossypol displaying superior efficacy and reduced toxicity. These studies illustrate the power of combining structure-based modeling with rational design to predict appropriate derivatives of lead compounds to be empirically tested and evaluated for bioactivity. Another approach to cancer drug discovery utilizes a cancer-specific promoter as readouts of the transformed state. The promoter region of Progression Elevated Gene-3 is such a promoter with cancer-specific activity. The specificity of this promoter has been exploited as a means of constructing cancer terminator viruses that selectively kill cancer cells and as a systemic imaging modality that specifically visualizes in vivo cancer growth with no background from normal tissues. Screening of small molecule inhibitors that suppress the Progression Elevated Gene-3-promoter may provide relevant lead compounds for cancer therapy that can be combined with further structure-based approaches leading to the development of novel compounds for cancer therapy.
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影响因子：
56.9
作者：
BABISS, LE;ZIMMER, SG;FISHER, PB
通讯作者：
FISHER, PB
DOI：
10.1073/pnas.0910936106
发表时间：
2009-12-15
影响因子：
11.1
作者：
Emdad, Luni;Lee, Seok-Geun;Fisher, Paul B.
通讯作者：
Fisher, Paul B.
影响因子：
11.2
作者：
Dash R;Richards JE;Su ZZ;Bhutia SK;Azab B;Rahmani M;Dasmahapatra G;Yacoub A;Dent P;Dmitriev IP;Curiel DT;Grant S;Pellecchia M;Reed JC;Sarkar D;Fisher PB
通讯作者：
Fisher PB
DOI：
10.1186/bcr2900
发表时间：
2011-06-14
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Clementz AG;Rogowski A;Pandya K;Miele L;Osipo C
通讯作者：
Osipo C
MDA-7/IL-24：IL-10基因家族的独特成员，促进了以癌为靶向的毒性。
影响因子：
13
作者：
Dash, Rupesh;Bhutia, Sujit K.;Azab, Belal;Su, Zhao-zhong;Quinn, Bridget A.;Kegelmen, Timothy P.;Das, Swadesh K.;Kim, Keetae;Lee, Seok-Geun;Park, Margaret A.;Yacoub, Adly;Rahmani, Mohammed;Emdad, Luni;Dmitriev, Igor P.;Wang, Xiang-Yang;Sarkar, Devanand;Grant, Steven;Dent, Paul;Curiel, David T.;Fisher, Paul B.
通讯作者：
Fisher, Paul B.