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A new kinase inhibitor for glioblastoma

A new kinase inhibitor for glioblastoma
一种新的胶质母细胞瘤激酶抑制剂
批准号:
10019480
负责人:
Raymond Daniel Blind
金额:
$18.49万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-09-17 至 2022-08-31

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中文摘要
翻译
摘要: 肿瘤抑制因子PTEN中和膜上的Class1 PI3-Kinase功能,导致 目前试图中和PTEN丢失的大量激酶抑制剂的开发工作 人类肿瘤。然而,我们在细胞核中发现了一个新的PTEN信号通路,即 与1类PI3-激酶完全解偶联。“脱钩”对抗癌药物至关重要 设计是因为如果肿瘤是由于核PTEN、1类PI3-激酶抑制剂的缺失而生长的 对这些肿瘤是无效的。事实上,PI3-激酶抑制剂往往不能挽救丢失的 PTEN在临床试验中的作用,原因尚不完全清楚。此外,这一新的PTEN 通路从来没有在任何癌症模型中被研究过,因为我们偶然发现了它,而 检查内分泌紊乱。在核途径中与PTEN相反的激酶是一种很差的 肌醇激酶超家族的特征成员,称为“肌醇多聚磷酸多激酶” (IPMK)。IPMK是一种核PIP2-激酶,结构上在所有人体组织中普遍表达 与1类PI3-激酶无关。Alfred Yung显示某些胶质母细胞瘤细胞系停止生长 当与胞核互补时,而不是胞质PTEN2。基于核途径,我们 假想的IPMK基因敲除可能在这些细胞中模拟核PTEN互补。的确, 初步数据显示CRSIPR敲除了IPMK表型核PTEN互补 这些细胞。野生型但不是激酶死亡的IPMK挽救了表型,提示IPMK 抑制剂可能是一种有效的治疗方法。这笔赠款开发了一种IPMK的化学遗传突变体,以 确定IPMK抑制剂是否对胶质母细胞瘤有效。未来的项目将使用 建立生理相关的小鼠模型以建立IPMK作为全面验证的目标 工业激酶抑制剂的努力。
英文摘要
Abstract: The tumor suppressor PTEN counteracts Class 1 PI3-kinase functions in membranes, leading to the massive kinase inhibitor development efforts currently attempting to counteract loss of PTEN in human tumors. However, we discovered a new PTEN signaling pathway in the nucleus that is completely decoupled from Class 1 PI3-kinases. The “decoupling” is important for anti-cancer drug design because if a tumor is growing due to loss of nuclear PTEN, Class 1 PI3-kinase inhibitors would be ineffective against those tumors. Indeed, PI3-kinase inhibitors often fail to rescue loss of PTEN function in clinical trials, for incompletely understood reasons. Further, this new PTEN pathway has never been studied in any model of cancer, as we discovered it fortuitously while examining endocrine disorders. The kinase opposing PTEN in the nuclear pathway is a poorly characterized member of the inositol kinase superfamily called “Inositol Polyphosphate Multikinase” (IPMK). IPMK is a nuclear PIP2-kinase with ubiquitous expression in all human tissues, structurally unrelated to Class 1 PI3-kinases. Alfred Yung showed certain glioblastoma cell lines halted growth when complemented with nuclear, not cytoplasmic PTEN2. Based on the nuclear pathway, we hypothesized IPMK knockout might mimic nuclear PTEN complementation in these cells. Indeed, preliminary data show CRSIPR knockout of IPMK phenocopies nuclear PTEN complementation in these cells. Wild type but not kinase-dead IPMK rescues the phenotype, suggesting an IPMK inhibitor could be an effective therapy. This grant develops a chemical genetic mutant of IPMK to determine if IPMK inhibitors would be effective in glioblastoma. Future projects will use physiologically relevant mouse models to establish IPMK as a validated target for full scale industrial kinase inhibitor efforts.
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Unconventional regulation of mTORC1 signaling by inositol phosphate: implications for nutrient-induced premature aging
  • 批准号:
    10372324
  • 项目类别:
  • 资助金额:
    $29.42万
  • 财政年份:
    2022
  • 负责人:
    Raymond Daniel Blind
  • 依托单位:
Unconventional regulation of mTORC1 signaling by inositol phosphate: implications for nutrient-induced premature aging
IPMK function in chromatin
Full-length LRH-1 structural regulation
国内基金
海外基金
Cd(II)在NH2-Agar/PSS双网络水凝胶上的吸附行为及资源化工艺研究
  • 批准号:
    51708204
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    25.0万元
  • 批准年份:
    2017
  • 负责人:
    周贵寅
  • 依托单位: