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首页> 外文学位 >Antagonism of the alpha-Helix Mediated Protein-Protein Interactions of the Bcl-2 and c-Myc Oncoprotein Families: Proteomimetic and Small-molecule Strategies.
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Antagonism of the alpha-Helix Mediated Protein-Protein Interactions of the Bcl-2 and c-Myc Oncoprotein Families: Proteomimetic and Small-molecule Strategies.

机译：Bcl-2和c-Myc癌蛋白家族的α-螺旋介导的蛋白质-蛋白质相互作用的拮抗作用：蛋白质模拟和小分子策略。

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摘要

The Bcl-2 oncoprotein family includes both anti- and pro-apoptotic proteins that are normally localized within the mitochondrial outer membrane. The over-expression of the anti-apoptotic proteins (such as Bcl-xL, Bcl-2, and Mcl-1) is associated with cancer and chemotherapeutic resistance. Pro-apoptotic Bcl-2 proteins (such as Bak and Bim) initiate the intrinsic apoptotic pathway via oligomerization at the mitochondrial membrane. However, in the presence of over-expressed anti-apoptotic Bcl-2 proteins, pro-apoptotic Bcl-2 proteins are sequestered and the intrinsic apoptotic pathway is antagonized. Specifically, the conserved BH3 alpha-helix of the pro-apoptotic proteins engage the hydrophobic binding crevices of the anti-apoptotic proteins largely through hydrophobic (i), (i + 3/4) and ( i + 7) residues on one face of the helix. Though potent inhibitors of Bcl-2 and Bcl-xL have been identified, chemically diverse pan-Bcl-2 and Mcl-1 specific inhibitors are lacking. Inspired by the recent advances in alpha-helix mimicry and fragment-based drug design, we have successfully synthesized potent (Ki ∼ 150 nM) pan-Bcl-2 inhibitors based on trisbenzamide and salicylate scaffolds and validated their activities in vitro..;The c-Myc oncoprotein is an intrinsicallydisordered (ID) transcription factor of a vast number of genes that are involved in cell proliferation and growth. Similar to anti-apoptotic Bcl-2 proteins, overexpression of c-Myc is associated with a myriad of cancers such as prostate, breast, and lung tumors. Though biologically inactive in its ID monomeric form, the transcriptional activation of c-Myc is initiated upon binding its obligatory protein partner Max. The transcriptionally active c-Myc-Max heterodimers recognize and bind the hexanucleotide sequence 5'-CACGTG-3' on dsDNA, where the transactivation domain of c-Myc recruits additional transcriptional machinery. Owing to its ID properties, in the absence of Max, c-Myc does not exhibit any secondary structure that may function as a basis for drug design. While several c-Myc specific inhibitors have been identified through high-throughput screening, few structure-activity relationship (SAR) studies have been reported. Towards developing potent c-Myc inhibitors, we conducted an SAR study on the c-Myc inhibitor 10074-G5 (IC50 = 146 uM), which resulted in the discovery of an improved inhibitor, JY-3-094 (IC50 = 33 muM) whose ester prodrugs exhibited potent cell activities (IC50 < 10 muM).
机译：Bcl-2癌蛋白家族包括通常位于线粒体外膜内的抗凋亡蛋白和促凋亡蛋白。抗凋亡蛋白（如Bcl-xL，Bcl-2和Mcl-1）的过度表达与癌症和化疗耐药有关。促凋亡的Bcl-2蛋白（例如Bak和Bim）通过线粒体膜的寡聚化来启动内在的凋亡途径。但是，在存在过量表达的抗凋亡Bcl-2蛋白的情况下，促凋亡Bcl-2蛋白被隔离，固有的凋亡途径被拮抗。具体而言，促凋亡蛋白的保守BH3α-螺旋主要通过抗性蛋白的一个面上的疏水（i），（i + 3/4）和（i + 7）残基与抗凋亡蛋白的疏水结合缝隙接合。螺旋线。尽管已鉴定出有效的Bcl-2和Bcl-xL抑制剂，但缺乏化学上多样化的pan-Bcl-2和Mcl-1特异性抑制剂。受α-螺旋模仿和基于片段药物设计的最新进展的启发，我们已经成功地基于三苯甲酰胺和水杨酸酯支架合成了有效的（Ki〜150 nM）pan-Bcl-2抑制剂，并在体外验证了它们的活性。 c-Myc癌蛋白是涉及细胞增殖和生长的大量基因的固有紊乱（ID）转录因子。与抗凋亡Bcl-2蛋白相似，c-Myc的过度表达与多种癌症（例如前列腺癌，乳腺癌和肺癌）有关。尽管其ID单体形式在生物学上无活性，但c-Myc的转录激活是在结合其必不可少的蛋白伴侣Max时开始的。具有转录活性的c-Myc-Max异二聚体识别并结合dsDNA上的六核苷酸序列5'-CACGTG-3'，其中c-Myc的反式激活域募集了额外的转录机制。由于其ID特性，在没有Max的情况下，c-Myc不会显示任何可作为药物设计基础的二级结构。尽管通过高通量筛选已鉴定出几种c-Myc特异性抑制剂，但很少报道结构-活性关系（SAR）研究。为了开发有效的c-Myc抑制剂，我们对c-Myc抑制剂10074-G5（IC50 = 146 uM）进行了SAR研究，从而发现了改良的抑制剂JY-3-094（IC50 = 33μM）。其酯前药表现出有效的细胞活性（IC50 <10μM）。

著录项

  • 作者

    Yap, Jeremy L.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Health Sciences Pharmacy.;Health Sciences Medicine and Surgery.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 364 p.
  • 总页数 364
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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