Identification of compounds selectively killing multidrug-resistant cancer cells.
Identification of compounds selectively killing multidrug-resistant cancer cells.
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DOI：
10.1158/0008-5472.can-09-2422
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发表时间：
2009-11-01
期刊：
影响因子：
11.2
通讯作者：
Szakács G
中科院分区：
文献类型：
--
作者：
Türk D;Hall MD;Chu BF;Ludwig JA;Fales HM;Gottesman MM;Szakács G
非常需要开发克服癌症中出现的多药耐药性的新型化学治疗剂。我们对国家癌症研究所的发展治疗计划（DTP）药物库进行了编目，以寻找在多药耐药（MDR）细胞中显示毒性增加的化合物。通过比较亲本细胞系与多药耐药衍生物的敏感性，我们确定了22种具有MDR选择活性的化合物。对结构同源物的分析导致鉴定出另外15种在Pgp表达细胞中显示毒性增加的药物。MDR选择性化合物的分析导致了构效关系（SAR）和药效团模型的制定。这种数据挖掘加上实验数据指出了与金属螯合有关的可能的作用机制。总之，MDR选择性化合物组的发现证明了MDR靶向治疗作为解决Pgp介导的多药耐药的新策略的发展领域的稳健性。
There is a great need for the development of novel chemotherapeutic agents that overcome the emergence of multidrug resistance in cancer. We catalogued the National Cancer Institute’s Developmental Therapeutics Program (DTP) drug repository in search of compounds showing increased toxicity in multidrug resistant (MDR) cells. By comparing the sensitivity of parental cell lines with multidrug resistant derivatives, we identified 22 compounds possessing MDR-selective activity. Analysis of structural congeners led to the identification of 15 additional drugs showing increased toxicity in Pgp-expressing cells. Analysis of MDR-selective compounds led to the formulation of structure activity relationships (SAR) and pharmacophore models. This data mining coupled with experimental data points to a possible mechanism of action linked to metal chelation. Taken together, the discovery of the MDR-selective compound set demonstrates the robustness of the developing field of MDR-targeting therapy as a new strategy for resolving Pgp-mediated multidrug resistance.