Discovery of a clinical stage multi-kinase inhibitor sodium (E)-2-{2-methoxy-5-[(2',4',6'-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): synthesis, structure-activity relationship, and biological activity.
Discovery of a clinical stage multi-kinase inhibitor sodium (E)-2-{2-methoxy-5-[(2',4',6'-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): synthesis, structure-activity relationship, and biological activity.
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DOI：
10.1021/jm200570p
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发表时间：
2011-09-22
影响因子：
7.3
通讯作者：
Reddy EP
中科院分区：
文献类型：
--
作者：
Reddy MV;Venkatapuram P;Mallireddigari MR;Pallela VR;Cosenza SC;Robell KA;Akula B;Hoffman BS;Reddy EP
细胞周期蛋白D在许多癌细胞中升高，在乳腺组织中靶向删除细胞周期蛋白D1基因可以保护小鼠免受乳腺癌的侵袭。因此，越来越多的人意识到这种新的非酶靶点用于癌症治疗。我们已经开发了一种新型的非烷基化苯乙烯苄基砜，它可以诱导多种癌细胞的细胞死亡，而不会影响正常细胞的增殖和存活。衍生化苯乙烯苄基砜的发展逻辑上遵循了我们实验室进行的肿瘤细胞毒性筛选，没有先验的目标谱。一些前体分子的修饰导致了有关肿瘤细胞毒性的先导优化。本文介绍了新型非烷基化(E)苯基苄基砜的合成及其构效关系，以及新型抗癌剂(E)-2-{2-甲氧基-5-[（2 ',4 ',6 ' -三甲氧基苯基磺酰基）甲基]苯基氨基}乙酸钠（ON 01910）的研制。Na)，该药物正在III期临床试验中，用于治疗与细胞周期蛋白D蛋白异常表达相关的骨髓增生异常综合征（MDS）。
Cyclin D proteins are elevated in many cancer cells and targeted deletion of Cyclin D1 gene in the mammary tissues protects mice from breast cancer. Accordingly, there is an increasing awareness of this novel non-enzymatic target for cancer therapeutics. We have developed novel, non-alkylating styryl benzyl sulfones that induce cell death in wide variety of cancer cells without affecting the proliferation and survival of normal cells. The development of derivatized Styryl Benzyl Sulfones followed logically from a tumor cell cytotoxicity screen performed in our laboratory that did not have an a priori target profile. Modifications of some of the precursor molecules led to lead optimization with regard to tumor cell cytotoxicity. In this report we describe the synthesis and structure-activity relationships of novel, non-alkylating (E) styryl benzyl sulfones, and the development of the novel anti-cancer agent sodium (E)-2-{2-methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl]phenylamino}-acetate (ON 01910.Na), which is in Phase III trials for myelodysplastic syndromes (MDS) associated with aberrant expression of cyclin D proteins.