Novel Single, Dual and Multitargeted Inhibitors of RTKs

受体酪氨酸激酶(RTK)利用三磷酸腺苷自动磷酸化序列中的特定酪氨酸残基 蛋白质的含量。许多肿瘤都有功能失调的RTK，通常过度表达，并导致不适当的信号转导。 因此，抑制RTK为癌症化疗提供了一个新的范式，几种RTK抑制剂是 目前作为抗肿瘤药物正在进行临床试验。 我们最近发现了一系列新型的RTK抑制剂，它们具有特殊的单、双和多通道。 对RTK的抑制作用。此外，我们还发现了一系列单独的新类似物，它们具有强大的 RTK抑制活性、抗血管生成活性以及二氢叶酸还原酶(DHFR)活性 探员们。在我们初步研究的基础上，我们建议对我们的先导类似物进行结构优化 提供最有效的药物，并提供构效关系研究(SAR)。 具体目标是合成化合物以优化对血管内皮细胞的抑制活性 生长因子受体-2(VEGFR-2)，抗内皮细胞生长因子受体(EGFR)，抗血小板衍生 生长因子受体-13(PDGFR-3)。合成类似物优化DHFR和VEGFR-2的抑制活性 单一特工。由于一些先导类似物对一种以上的RTK具有多种抑制作用，因此SAR 在这些研究中生成的数据还将允许描述单个或多个所需的结构要求 对RTK的抑制活性。所有的化合物都将在合作的基础上进行体外评估 对VEGFR-2、EGFR、PDGFR-β、FGFR的抑制活性和CAM抗血管生成活性(DR。 Michael Ihnat)和针对DHFR的适当类似物(Roy L.Kisliuk博士)。适当的类比也将是 针对过度表达EGFR的A431细胞进行评估(Ihnat博士)。 此外，我们从我们的初步研究中选择了三个类似物在B16小鼠身上进行体内试验 黑色素瘤肿瘤模型的抗肿瘤活性。至少将从这项研究中选择另外四个类似物用于 活体评估(Michael Inhat博士)。 这项研究应该提供具有单、双或多靶点功能的结构优化的类似物 RTK的抑制剂以及VEGFR-2和DHFR的类似物作为抗肿瘤药物具有不同的光谱 抗肿瘤活性，也许可以提供类似物，可以推进到针对实体瘤的临床试验。

Receptor tyrosine kinases (RTKs) utilize ATP to autophosphorylate specific tyrosine residues in the sequence of proteins. A variety of tumors have dysfunctional RTKs, often overexpressed, and result in inappropriate signaling. Thus inhibition of RTKs have provided a new paradigm for cancer chemotherapy and several RTK inhibitors are currently in clinical trials as antitumor agents. We recently discovered a series of novel RTK inhibitors which have exceptional single, dual and multi- inhibitory effects against RTKs. In addition, we also discovered a separate series of novel analogs which possess potent RTK inhibitory activity, antiangiogenic activity along with dihydrofolate reductase (DHFR) inhibitory activity in single agents. On the basis of our preliminary studies, we propose to carry out a structure optimization of our lead analogs to afford the most effective agents and to provide a structure-activity relationship study (SAR). The specific aims are to synthesize compounds to optimize inhibitory activity against vascular endothelial growth factor receptor-2 (VEGFR-2), against endothelial growth factor receptor (EGFR), against platelet-derived growth factor receptor-13 (PDGFR-[3). To synthesize analogs to optimize DHFR and VEGFR-2 inhibitory activity in single agents. Since some of the lead analogs have multiple inhibitory effects against more than one RTK, the SAR generated in these studies will also allow a delineation of structural requirements necessary for single or multiple inhibitory activity against RTKs. All of the compounds will be evaluated on a collaborative basis for in vitro inhibitory activity against VEGFR-2, EGFR, PDGFR-_, FGFR and the CAM assay for antiangiogenic activity (Dr. Michael ihnat) and appropriate analogs against DHFR (Dr. Roy L. Kisliuk). Appropriate analogs will also be evaluated against A431 cells that overexpress EGFR (Dr. Ihnat). In addition, we have selected three analogs from our preliminary studies for in vivo assay in the B 16 mouse melanoma tumor model for antitumor activity. At least four additional analogs from this study will be selected for in vivo evaluation (Dr. Michael Inhat). This study should provide structurally optimized analogs which function as single, dual or multitargeted inhibitors of RTKs as well as analogs for VEGFR-2 and DHFR as antitumor agents with a different spectrum of antitumor activity and perhaps afford analogs that can be advanced to clinical trials against solid tumors.