Generation of Pim kinase inhibitors based on structural and post-transcriptional analysis

基于结构和转录后分析的 Pim 激酶抑制剂的生成

• 批准号: 22650238
• 负责人: FUJITA Naoya
• 金额: $ 2.22万
• 依托单位: 公益財団法人がん研究会 (2011)Japanese Foundation For Cancer Research (2010)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22650238/
• 关键词: Pimキナーゼ; 結晶構造解析; 阻害剤; p27^<Kip1>; がん; 生体分子; シグナル; Pim

The serine/threonine kinase Pim-1 plays an important role in cell cycle progression and apoptosis inhibition, resulting in prostate tumorigenesis. Therefore, Pim-1 inhibition has been expected to be an attractive target for developing new anti-cancer drugs. However, no small compounds targeting Pim-1 have progressed to clinical use because of their lack of specificity. Here we analyzed the X-ray crystal structure of Pim-1 in complex with p27^<Kip1> peptide at 1.6 A resolution. Adding eight tandem Arg residues, R8, we generated a new cell-permeable Pim-1-inhibitory p27^<Kip1> peptide that could interfere with the binding of Pim-1 to its substrates and act as an anti-cancer drug. Treatment of prostate cancer DU145 with the peptide induces G1 arrest and subsequently apoptosis in vitro. The peptide could also inhibit tumor growth in in vivo prostate cancer xenograft models.

丝氨酸/苏氨酸激酶PIM-1在细胞周期进程和凋亡抑制中起重要作用，导致前列腺肿瘤发生。因此，预计PIM-1抑制是开发新抗癌药物的有吸引力的靶标。然而，由于缺乏特异性，靶向PIM-1的小化合物已经发展为临床使用。在这里，我们分析了PIM-1与P27^<kip1>肽在1.6 A分辨率的复合物中的X射线晶体结构。添加了八个串联ARG残基R8，我们产生了一种新的可渗透细胞PIM-1抑制性P27^<kip1>肽，该肽可能会干扰PIM-1与其底物的结合并充当抗癌药物。用肽治疗前列腺癌DU145可在体外诱导G1停滞，然后在体外凋亡。该肽还可以抑制体内前列腺癌异种移植模型中的肿瘤生长。

项目成果

血小板凝集促進因子Aggrusを標的とした抗体による血行性転移の阻害

靶向血小板聚集促进因子 Aggrus 的抗体抑制血行转移

• 发表时间: 2011
• 作者: 高木聡;藤田直也
• 通讯作者: 藤田直也

The Novel Metastasis Promoter Merm1/Wbscr22 Enhances Tumor Cell Survival in the Vasculature by Suppressing Zac1/p53-Dependent Apoptosis

• DOI: 10.1158/0008-5472.can-10-2695
• 发表时间: 2011-02-01
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: Nakazawa, Youya;Arai, Hiroyuki;Fujita, Naoya
• 通讯作者: Fujita, Naoya

Transforming growth factor-B decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells.

转化生长因子-B 减少弥漫型胃癌细胞内的癌症起始细胞群。

• 发表时间: 2011
• 期刊: Oncogene
• 影响因子: 8
• 作者: Suzuki;A.;U. Tsunogai;F. Nakagawa;D. D. Komatsu;H. Shibata;K. Fukuzawa;Shogo Ehata
• 通讯作者: Shogo Ehata

Cell-permeable carboxy-terminal p27^<Kip1> peptide exhibits anti-tumor activity by inhibiting Pim-1 kinase.

细胞可渗透的羧基末端 p27^<Kip1> 肽通过抑制 Pim-1 激酶表现出抗肿瘤活性。

• 发表时间: 2011
• 期刊: J.Biol.Chem.
• 作者: Konno;U.;U. Tsunogai;D. D. Komatsu;S. Daita;F. Nakagawa;A. Tsuda;T. Matsui;Y.-J. Eum and K. Suzuki;Daisuke Morishita
• 通讯作者: Daisuke Morishita

転移先微小環境内におけるがんの生存と血行性転移促進

转移微环境中癌症的存活和血行转移的促进

• 发表时间: 2011
• 作者: Satoshi Hirakawa;Shigeki Higashiyama;鈴木敦之,角皆潤,中川書子,小松大祐,柴田英昭,福澤加里部;藤田直也
• 通讯作者: 藤田直也