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Signalling approaches to inhibition of cellular proliferation

机译:抑制细胞增殖的信号传导方法

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There has been considerable progress in elucidating the mechanisms by which extracellular signals are transduced via cell surface receptors to trigger changes in gene expression determining the growth and differnetiated state of the cell. Efforts to understand and target the mechanisms that underlie the development of abnormal proliferative diseases including vascular injury and cancer are under intense study [1,2]. We have targeted several strategies to inhibit cellular proliferation including blockade of platelet derived growth factor (PDFG) mediated mitogenic signalling and secondly with a downstream target by interfering with ras protein function via the enzyme ras farnesyl with a downstream target by interfering with ras protein cellular acting peptide inhibitors of the association of hte C-terminal SH2 domain of the p85 subunit of phosphatidyl 3-kinase (PI_3 kinase) with the PDGF- beta receptor from the phosphorylated pentapeptide Tyr(PO_3H_2)~751-Val-Pro-Met-Leu (IC_50=0.67 pM) have led to potent tetra- and tripeptide inhibitors. In the second signalling strategy, development of potent peptidomimetic inhibitors of the enzyme FTase are presented. Truncated tri-and dipeptides and peptidomimetics with cellular activity derived from the pentapeptide lead PD 083176 (Cbz-His-Tyr(OBn)-Ser(OBn)-TrpDala-NH_2) (IC_50=17nM) have been discovered.
机译:阐明了通过细胞表面受体转导细胞外信号以触发基因表达的变化来确定细胞的生长和不同的状态的机制存在相当大的进展。努力理解和瞄准利益强度发展的机制,包括血管损伤和癌症的异常增殖性疾病(癌症)是强烈的研究[1,2]。我们针对几种策略来抑制细胞增殖,包括阻断血小板衍生的生长因子(PDFG)介导的促丝胶信号传导,并通过通过干扰Ras蛋白细胞作用干扰下游靶的酶Ras Farneryyl在下游靶向下游靶标HTE C-末端SH2孔的肽抑制剂HTE C-末端SH2域的P85亚酶(PI_3激酶)与来自磷酸化五肽TYR(PO_3H_2)〜751-VAL-PRE-MET-LEU的PDGF-β受体( IC_50 = 0.67 PM)导致有效的四肽和三肽抑制剂。在第二信号传导策略中,提出了酶FTase的有效肽抑制剂的发展。已经发现截短的三肽和二肽和肽瘤和肽测量衍生自五肽铅PD 083176(CBZ-HIS-TYR(OBN)-SER(OBN)-TRPDALA-NH_2)(IC_50 = 17nm)的细胞活性。

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