AEE788: A dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity
AEE788: A dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity
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DOI：
10.1158/0008-5472.can-03-3681
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发表时间：
2004-07-15
期刊：
影响因子：
11.2
通讯作者：
Caravatti, G
中科院分区：
文献类型：
--
作者：
Traxler, P;Allegrini, PR;Caravatti, G
在许多肿瘤类型(乳腺癌、肺癌、卵巢癌、前列腺癌、胶质瘤、胃癌和头颈部鳞癌)中，表皮生长因子受体(EGFR)和ErbB2的异常表达与疾病进展和患者预后不良有关。此外，在非小细胞肺癌、胶质母细胞瘤和乳腺肿瘤中也发现了一种具有结构性活性的EGFR III型缺失突变体。因此，EGFR家族的成员被视为抗癌的有希望的治疗靶点。在类似的静脉中，血管内皮生长因子(VEGF)受体激酶也是抗血管生成治疗策略方面的有希望的靶点。通过对7H-吡咯并[2，3-d]嘧啶铅支架进行优化得到的AEE788，在分离的酶水平和细胞系统中都是一种有效的表皮生长因子(EGF)和血管内皮生长因子受体酪氨酸激酶家族成员的联合抑制剂。在酶水平，AEE788对EGFR和VEGF受体酪氨酸激酶的抑制作用IC50范围为：EGFR 2 nm、ErbB2 6 nm、KDR 77 nm和Flt-159 nm)。在细胞内，生长因子诱导的表皮生长因子受体和ErbB2的磷酸化也被有效地抑制(IC(50)S：11和220 nm)。AEE788对一系列高表达EGFR和ErbB2的细胞(包括EGFRvIII依赖的细胞)具有抗增殖活性，并抑制表皮生长因子和血管内皮生长因子刺激的人脐静脉内皮细胞的增殖。这些特性与良好的药代动力学特征相结合，在许多癌症动物模型中具有强大的抗肿瘤活性，包括过度表达EGFR和/或ErbB2的肿瘤。给荷瘤小鼠口服AEE788后，肿瘤组织中的化合物水平较高且持续存在。此外，AEE788有效地抑制了生长因子诱导的肿瘤中EGFR和ErbB2的磷酸化达72小时，这一现象与间歇治疗方案的抗肿瘤效果有关。值得注意的是，AEE788还在海洋植入模型中抑制了血管内皮生长因子诱导的血管生成。通过动态增强磁共振成像方法测量肿瘤血管通透性和间质渗漏间隙，也显示了抗血管生成活性。综上所述，这些数据表明，AEE788具有潜在的抗癌药物的作用，靶向肿瘤细胞增殖和血管生成参数。因此，AEE788目前正处于肿瘤学的I期临床试验。
Aberrant epidermal growth factor receptor (EGFR) and ErbB2 expression are associated with advanced disease and poor patient prognosis in many tumor types (breast, lung, ovarian, prostate, glioma, gastric, and squamous carcinoma of head and neck). In addition, a constitutively active EGFR type III deletion mutant has been identified in non-small cell lung cancer, glioblastomas, and breast tumors. Hence, members of the EGFR family are viewed as promising therapeutic targets in the fight against cancer. In a similar vein, vascular endothelial growth factor (VEGF) receptor kinases are also promising targets in terms of an antiangiogenic treatment strategy. AEE788, obtained by optimization of the 7H-pyrrolo[2,3-d]pyrimidine lead scaffold, is a potent combined inhibitor of both epidermal growth factor (EGF) and VEGF receptor tyrosine kinase family members on the isolated enzyme level and in cellular systems. At the enzyme level, AEE788 inhibited EGFR and VEGF receptor tyrosine kinases in the nM range IC50: EGFR 2 nm, ErbB2 6 nm, KDR 77 nm, and Flt-159 nm). In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited (IC(50)s: 11 and 220 nm, respectively). AEE788 demonstrated antiproliferative activity against a range of EGFR and ErbB2-overexpressing cell lines (including EGFRvIII-dependent lines) and inhibited the proliferation of epidermal growth factor- and VEGF-stimulated human umbilical vein endothelial cells. These properties, combined with a favorable pharmacokinetic profile, were associated with a potent antitumor activity in a number of animal models of cancer, including tumors that overexpress EGFR and or ErbB2. Oral administration of AEE788 to tumor-bearing mice resulted in high and persistent compound levels in tumor tissue. Moreover, AEE788 efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. Strikingly, AEE788 also inhibited VEGF-induced angiogenesis in a marine implant model. Antiangiogenic activity was also apparent by measurement of tumor vascular permeability and interstitial leakage space using dynamic contrast enhanced magnetic resonance imaging methodology. Taken together, these data indicate that AEE788 has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters. Consequently, AEE788 is currently in Phase I clinical trials in oncology.