Novel Single, Dual and Multitargeted Inhibitors of RTKs

受体酪氨酸激酶（RTK）利用ATP使序列中的特定酪氨酸残基自磷酸化， 蛋白质。多种肿瘤具有功能失调的RTK，通常过表达，并导致不适当的信号传导。 因此，RTK的抑制已经为癌症化疗提供了新的范例，并且几种RTK抑制剂被用于治疗癌症。 目前作为抗肿瘤药物在临床试验中。 我们最近发现了一系列新的RTK抑制剂，它们具有独特的单，双和多功能， 对RTK的抑制作用。此外，我们还发现了一系列新的类似物， RTK抑制活性、抗血管生成活性沿着二氢叶酸还原酶（DHFR）抑制活性， 剂.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，并提供结构-活性关系研究（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），抗内皮生长因子受体（EGFR），抗血小板源性 生长因子受体-13（PDGFR-）[3]。为了合成类似物以优化DHFR和VEGFR-2抑制活性， 单一代理由于一些先导类似物对不止一种RTK具有多重抑制作用，因此SAR 在这些研究中产生的，也将允许划定的结构要求所需的单一或多个 对RTK的抑制活性。所有化合物将在体外协作基础上进行评价 针对VEGFR-2、EGFR、PDGFR-1、FGFR的抑制活性和抗血管生成活性的CAM测定（Dr. Michael ihnat）和针对DHFR的适当类似物（Roy L. Kisliuk）。适当的类似物也将被 针对过表达EGFR的A431细胞进行评估（Dr. Ihnat）。 此外，我们从我们的初步研究中选择了三种类似物用于B 16小鼠的体内测定 黑色素瘤肿瘤模型的抗肿瘤活性。将从本研究中选择至少四种额外的类似物用于 体内评价（Michael Inhat博士）。 这项研究应提供结构优化的类似物，其功能为单，双或多靶点 RTKs抑制剂以及VEGFR-2和DHFR的类似物作为具有不同谱的抗肿瘤剂， 抗肿瘤活性，并可能提供类似物，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.