Novel SET Antagonists for the Treatment of Chronic Myelogenous Leukemia

慢性粒细胞白血病(CML)是一种多能造血干细胞的疾病，具有两个不同的阶段。骨髓增殖性慢性期持续时间延长，紧随其后的是一场迅速致命的白血病危机。在慢性粒细胞白血病中，染色体易位导致产生Philadelphia染色体(PH1)，在该染色体中，bcr蛋白与Abl激酶融合形成bcr/abl癌基因，这是Abl激酶的一种结构性激活形式。ABL的这种结构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，CML的治疗取得了进展，但最近有报道称，对格列卫耐药的CML越来越受到关注。进展到急变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，Perroti和他的同事们证明，BCR/ABL活性水平的增加也会导致CML和PH1(+)急性淋巴细胞白血病急性期SET蛋白的过度表达。由于其对肿瘤抑制蛋白磷酸酶2A(PP2A)的有效抑制作用，SET被称为蛋白磷酸酶2A抑制物-2(I2PP2A)。SET的过表达导致对PP2A的强烈抑制，从而抑制PP2A通过去磷酸化来发挥其对信号蛋白失活的调节作用。 Oncotie制药公司已经开发出在体外和体内具有强大抗炎活性的新型化合物)。在机制研究中，我们最近发现这些多肽与SET结合，并具有激活细胞内PP2A酶活性的能力。基于这些数据，我们推测我们的先导化合物(OP449)可能对CML和其他以PP2A活性受损为特征的血液和非血液系统恶性肿瘤患者提供治疗益处。我们已经确定OP449抑制BCR/ABL+K562 CML细胞系的增殖和诱导细胞凋亡，抑制原代患者来源的CML细胞的集落形成，并且对正常CD34+细胞没有细胞毒性。我们现在试图扩展这些研究，以确定OP449是否对耐药CML细胞和急变期CML细胞具有细胞毒性；评估PP2A在这些细胞中的激活；确定OP449处理对BCR/ABL、ERK、AKT和STAT5磷酸化的影响；以及在CML体内模型中抑制生长。

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.