Novel SET Antagonists for the Treatment of Chronic Myelogenous Leukemia

用于治疗慢性粒细胞白血病的新型 SET 拮抗剂

基本信息

  • 批准号:
    8643318
  • 负责人:
  • 金额:
    $ 14.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-04-05 至 2014-05-31
  • 项目状态:
    已结题

项目摘要

Chronic Myelogenous Leukemia (CML) affects nearly 14,000 patients worldwide and is a disorder of the pluripotent hematopoietic stem cells with two distinct phases. The protracted myelopoliferative chronic phase is followed by a rapidly fatal blast crisis. In CML, a chromosomal translocation leads to production of the Philadelphia Chromosome (Ph1) in which the BCR protein is fused to the Abl kinase to form the BCR/ABL oncogene, a constitutively activated form of the Abl kinase. This constitutive activation of Abl has been shown to be sufficient for induction of chronic phase CML. Although progress has been made in treatment of CML with the introduction of Gleevec and other inhibitors of BCR/ABL, recently however, Gleevec resistant CML has been reported and is a growing concern. Patients that progress into blast phase also experience a resistance to Gleevec and other BCR/ABL inhibitors (i.e. dasatinib and nilotinib. Recently, Perrotti and coworkers demonstrated that increased levels of BCR/ABL activity also results in the overexpression of the protein SET in the blast phase of CML and in the PH1(+) acute lymphoblastic leukemia. Due to its potent inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A) SET is known as Inhibitor-2 of Protein Phosphatase 2A (I2PP2A). Overexpression of SET results in strong inhibition of PP2A, thereby inhibiting the ability of PP2A to perform its regulatory role in deactivating signaling proteins by dephosphorylation. Oncotide Pharmaceuticals has developed novel compounds) that have potent anti-inflammatory activity in vitro and in vivo. In mechanistic studies we recently discovered that these peptides bind to SET and have the ability to activate PP2A enzymatic activity in the cell. Based on this data, we postulated that our lead compound (OP449) may provide therapeutic benefits in patients with CML and other hematologic and non-hematologic malignancies characterized by impaired PP2A activity. We have determined that OP449 suppresses proliferation and induces apoptosis in the BCR/ABL+ K562 CML line, inhibits colony formation by primary patient-derived CML cells, and does is not cytotoxic to normal CD34+ cells. We now seek to extend these studies to determine if OP449 is cytotoxic to drug-resistant CML cells and blast phase CML cells; evaluate the activatin of PP2A in these cells; determine the effect of OP449 treatment on phosphorylation of BCR/ABL, ERK, AKT and STAT5; an inhibit growth in an in vivo model of CML.
慢性骨髓性白血病(CML)是一种多能性造血干细胞疾病,有两个不同的阶段,在全球范围内影响了近14000名患者。延长的髓细胞增殖慢性期之后是迅速致命的细胞危象。在慢性粒细胞白血病中,染色体易位导致费城染色体(Ph1)的产生,其中BCR蛋白与Abl激酶融合形成BCR/ Abl癌基因,这是Abl激酶的组成性激活形式。这种Abl的组成性激活已被证明足以诱导慢性期CML。尽管随着格列卫和其他BCR/ABL抑制剂的引入,慢性粒细胞白血病的治疗取得了进展,但最近有报道称,格列卫耐药的慢性粒细胞白血病日益受到关注。进入母细胞期的患者也会对格列卫和其他BCR/ABL抑制剂(即达沙替尼和尼洛替尼)产生耐药性。最近,Perrotti和同事证明BCR/ABL活性水平的增加也会导致CML细胞期和PH1(+)急性淋巴细胞白血病中SET蛋白的过度表达。由于其对肿瘤抑制蛋白磷酸酶2A (PP2A)的有效抑制,SET被称为蛋白磷酸酶2A (I2PP2A)的抑制剂-2。SET过表达导致PP2A的强烈抑制,从而抑制PP2A通过去磷酸化使信号蛋白失活的调节能力。

项目成果

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Dale J Christensen其他文献

Dale J Christensen的其他文献

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{{ truncateString('Dale J Christensen', 18)}}的其他基金

Development of a shelf-stable universal mucosal HA-vaccine for the prevention of influenza
开发用于预防流感的储存稳定的通用粘膜HA疫苗
  • 批准号:
    10600541
  • 财政年份:
    2023
  • 资助金额:
    $ 14.98万
  • 项目类别:
Targeting c-Myc and Akt with PP2A reactivation therapy for the treatment of breas
通过 PP2A 再激活疗法靶向 c-Myc 和 Akt 治疗乳腺癌
  • 批准号:
    8454718
  • 财政年份:
    2013
  • 资助金额:
    $ 14.98万
  • 项目类别:
Novel SET Antagonists for the Treatment of Chronic Myelogenous Leukemia
用于治疗慢性粒细胞白血病的新型 SET 拮抗剂
  • 批准号:
    8253135
  • 财政年份:
    2012
  • 资助金额:
    $ 14.98万
  • 项目类别:
High Throughput Screen for Novel Anti-Rheumatic Compounds
新型抗风湿化合物的高通量筛选
  • 批准号:
    7999598
  • 财政年份:
    2010
  • 资助金额:
    $ 14.98万
  • 项目类别:
Novel Screen for Targeted CLL Therapeutics
靶向 CLL 治疗的新型筛选
  • 批准号:
    7746678
  • 财政年份:
    2009
  • 资助金额:
    $ 14.98万
  • 项目类别:
Therapeutic for Intracerebral Hemorrhage
脑出血的治疗
  • 批准号:
    7741461
  • 财政年份:
    2009
  • 资助金额:
    $ 14.98万
  • 项目类别:
Novel Targeted Therapy for CLL
CLL 的新型靶向治疗
  • 批准号:
    7612201
  • 财政年份:
    2008
  • 资助金额:
    $ 14.98万
  • 项目类别:
Novel Therapy for Sepsis
败血症的新疗法
  • 批准号:
    7219851
  • 财政年份:
    2007
  • 资助金额:
    $ 14.98万
  • 项目类别:
Novel Treatment for Parkinson's Disease
帕金森病的新疗法
  • 批准号:
    7326049
  • 财政年份:
    2007
  • 资助金额:
    $ 14.98万
  • 项目类别:
Novel Therapeutic for SAH
SAH 的新疗法
  • 批准号:
    7404911
  • 财政年份:
    2007
  • 资助金额:
    $ 14.98万
  • 项目类别:

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