Studies on inhibitors for epidermal growth factor receptor based on oligopeptides which imitated pseudosubstrates

基于模拟假底物寡肽的表皮生长因子受体抑制剂的研究

• 批准号: 18590032
• 负责人: KURODA Yoshihiro
• 金额: $ 2.57万
• 依托单位: Himeji Dokkyo University (2007)Kyoto University (2006)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590032/
• 关键词: epidermal growth factor receptor; EGFR; autophosphorylation; ATP-non・competitive inhibitor; oligopeptide; docking simulation; NYQQN; psuedosubstrate; 阻害剤; 擬似基質

1. Inhibition of autophosphorylation of epidermal growth factor receptor (EGFR) by oligopeptides having amino acid sequences around autophosphorylation sites of EGFR (Tyr992, Tyr1068, Tyr1148, Tyr1173) were studied. The peptides Ac-VPEYINQ-NH2, Ac-DYQQD-NH2, and Ac-ENAEYLR-NH2, which originate from Tyr1068, Tyr1148, and Tyr1173, respectively, were found to be effective in inhibiting autophosphorylation of EGFR. Effects of the replacement of tyrosine residue in each peptide by alanine, leucine, phenylalanine, or phosphotyrosine on inhibitory potencies of autophosphorylation were studied. Aromatic rings in the peptides were found to be essential for inhibitory potencies.2. Replacement of acidic amino acids in DYQQD and ENAEYLR by neutral amino acids greatly increased inhibitory potencies.3. Docking simulations showed that DYQQD and QNAQYLR are ATP-competitive inhibitors, whereas ENAEYLR and NYQQN are ATP-non-competitive inhibitors.4. Effects of ATP concentrations on inhibitory potencies were studied to see whether the oligopeptides are ATP-competitive inhibitors. Experimental results supported the results predicted by the docking simulations.5. It is expected that ATP-non-competitive inhibitors (ENAEYLR and NYQQN) are specific inhibitors for EGFR. Thus, especially, NYQQN is a promising seed for developing therapeutic agents for breast and lung cancers.

1.研究了表皮生长因子受体（EGFR）自磷酸化位点（Tyr 992，Tyr 1068，Tyr 1148，Tyr 1173）周围氨基酸序列的寡肽对EGFR自磷酸化的抑制作用。发现分别源自Tyr 1068、Tyr 1148和Tyr 1173的肽Ac-VPEYINQ-NH 2、Ac-DYQQD-NH 2和Ac-ENAEYLR-NH 2有效抑制EGFR的自磷酸化。研究了用丙氨酸、亮氨酸、苯丙氨酸或磷酸酪氨酸取代每种肽中的酪氨酸残基对自磷酸化抑制效力的影响。发现肽中的芳香环对于抑制效力是必需的。将DYQQD和ENAEYLR中的酸性氨基酸替换为中性氨基酸后，抑制作用大大增强.对接模拟表明，DYQQD和QNAQYLR是ATP竞争性抑制剂，而ENAEYLR和NYQQN是ATP非竞争性抑制剂.研究了ATP浓度对抑制效力的影响，以确定寡肽是否为ATP竞争性抑制剂。实验结果支持了对接仿真的预测结果.预期ATP非竞争性抑制剂（ENAEYLR和NYQQN）是EGFR的特异性抑制剂。因此，特别是，NYQQN是一个有前途的种子开发乳腺癌和肺癌的治疗药物。

项目成果

Inhibition of autophosphorylation of epidermal growth factor receptor by inhibitory peptides not employing an ATP-competitive mechanism

不采用 ATP 竞争机制的抑制肽抑制表皮生长因子受体的自身磷酸化

• 发表时间: 2008
• 作者: Yuji Mori;Hiroki Furuta;Naoki Hiramatsu;Mineo Abe;Mineo Abe;Mineo Abe;Mineo Abe;阿部 峰大;Mineo Abe
• 通讯作者: Mineo Abe

Inhibition of autuphosphorylation of epidermal growth factor receptor by a small peptide not employing an ATP-competitive mechanism

不采用 ATP 竞争机制的小肽抑制表皮生长因子受体的自磷酸化

• 发表时间: 2008
• 期刊: Biopolymers 89
• 作者: Yuji Mori;Hiroki Furuta;Naoki Hiramatsu;Mineo Abe;Mineo Abe
• 通讯作者: Mineo Abe

上皮成長因子受容体阻害ペプチドのチロシン残基の置換による自己リン酸化抑制効果への影響

表皮生长因子受体抑制肽酪氨酸残基取代对自身磷酸化抑制作用的影响

• 发表时间: 2006
• 作者: Yuji Mori;Hiroki Furuta;Naoki Hiramatsu;Mineo Abe;Mineo Abe;Mineo Abe;Mineo Abe;阿部 峰大;Mineo Abe;加藤 真基;Masaki Kato;加藤 真基;Masaki Kato;阿部 峰大
• 通讯作者: 阿部 峰大

非ATP競合型ペプチド阻害剤による上皮成長因子受容体の自己リン酸化抑制効果

非 ATP 竞争性肽抑制剂抑制表皮生长因子受体自身磷酸化

• 发表时间: 2008
• 作者: Yuji Mori;Hiroki Furuta;Naoki Hiramatsu;Mineo Abe;Mineo Abe;Mineo Abe;Mineo Abe;阿部 峰大
• 通讯作者: 阿部 峰大

活性化ループ上のアミノ酸配列を元にしたオリゴペプチドによるインスリン受容体の自己リン酸化抑制

基于激活环上氨基酸序列的寡肽对胰岛素受体自身磷酸化的抑制

• 发表时间: 2007
• 作者: Yuji Mori;Hiroki Furuta;Naoki Hiramatsu;Mineo Abe;Mineo Abe;Mineo Abe;Mineo Abe;阿部 峰大;Mineo Abe;加藤 真基;Masaki Kato;加藤 真基
• 通讯作者: 加藤 真基