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首页> 外文期刊>Journal of Medicinal Chemistry >Design of peptidomimetics that inhibit the association of phosphatidylinositol 3-kinase with platelet-derived growth factor-beta receptor and possess cellular activity.
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Design of peptidomimetics that inhibit the association of phosphatidylinositol 3-kinase with platelet-derived growth factor-beta receptor and possess cellular activity.

机译：拟肽的设计可抑制磷脂酰肌醇3激酶与血小板衍生的生长因子β受体的缔合，并具有细胞活性。

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摘要

Phosphorylated tyrosine residues of growth factor receptors that associate with intracellular proteins containing src-homology 2 (SH2) domains are integral components in several signal transduction pathways related to proliferative diseases such as cancer, atherosclerosis, and restenosis. In particular, a phosphorylated pentapeptide [pTyr751-Val-Pro-Met754-Leu (pTyr = phosphotyrosine)] derived from the primary sequence of platelet-derived growth factor-beta (PDGF-beta) receptor blocks the association of the C-terminal SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) to PDGF-beta receptor with an IC50 of 0.445 +/- 0.047 microM. Further evaluation of the structure-activity relationships for pTyr751-Val-Pro-Met-Leu resulted in the design of smaller peptidomimetics with enhanced affinity including Ac-pTyr-Val-Ala-N(C6H13)2 (IC50 = 0.076 +/- 0.010 microM). In addition, the phosphotyrosine residue was replaced with a difluorophosphonate derivative [4-phosphono(difluoromethyl)phenylalanine (CF2Pmp)] which has been shown to be stable to cellular phosphatases. The extracellular administration of either CF2Pmp-Val-Pro-Met-Leu or Ac-CF2Pmp-Val-Pro-Met-NH2 in a whole cell assay resulted in specific inhibition of the PDGF-stimulated association from the C-terminal SH2 domain of the p85 subunit of PI 3-kinase to the PDGF-beta receptor in a dose-dependent manner. These compounds were also effective in inhibiting GLUT4 translocation, c-fos expression, and cell membrane ruffling in single-cell microinjection assay.
机译：与含有src-homology 2（SH2）域的细胞内蛋白相关的生长因子受体的磷酸化酪氨酸残基是与诸如癌症，动脉粥样硬化和再狭窄等增生性疾病相关的几种信号转导途径中不可或缺的组成部分。尤其是，源自血小板衍生的生长因子-β（PDGF-β）受体一级序列的磷酸化五肽[pTyr751-Val-Pro-Met754-Leu（pTyr =磷酸酪氨酸）]会阻断C末端SH2的缔合磷脂酰肌醇3-激酶（PI 3-激酶）的p85亚基对PDGF-β受体的结构域，IC50为0.445 +/- 0.047 microM。对pTyr751-Val-Pro-Met-Leu的构效关系的进一步评估导致设计了具有增强亲和力的较小拟肽，包括Ac-pTyr-Val-Ala-N（C6H13）2（IC50 = 0.076 +/- 0.010 microM）。另外，磷酸酪氨酸残基被二氟膦酸酯衍生物[4-膦酰基（二氟甲基）苯丙氨酸（CF2Pmp）]代替，该衍生物已显示对细胞磷酸酶稳定。在全细胞分析中对CF2Pmp-Val-Pro-Met-Leu或Ac-CF2Pmp-Val-Pro-Met-NH2进行细胞外给药可特异性抑制PDGF刺激的C末端SH2结构域的缔合。 PI 3-激酶的p85亚基与PDGF-β受体呈剂量依赖性。这些化合物在单细胞显微注射测定中也有效抑制GLUT4易位，c-fos表达和细胞膜起皱。

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