Novel Single, Dual and Multitargeted Inhibitors of RTKs
RTK 的新型单靶点、双靶点和多靶点抑制剂
基本信息
- 批准号:7163018
- 负责人:
- 金额:$ 27.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-01-20 至 2008-12-31
- 项目状态:已结题
- 来源:
- 关键词:Amino Acid SequenceAngiogenesis InhibitorsArtsBenzofuransBindingBiologicalBiological AssayCell LineCell ProliferationCellsChemotherapy-Oncologic ProcedureClinical TrialsCollaborationsComplement component C1sCytostaticsCytotoxic agentDifferentiation and GrowthDihydrofolate ReductaseDihydrofolate Reductase InhibitorEarEndothelial Growth Factors ReceptorEpidermal Growth Factor ReceptorEvaluationEventFibroblast Growth Factor ReceptorsGoalsGrowth Factor ReceptorsH 89HumanIn VitroIndolesIsomerismIsoquinolinesLeadLiteratureMalignant NeoplasmsModelingMusNeoplasm MetastasisNumbersPD153035PDGFRB genePeptide Sequence DeterminationPlatelet-Derived Growth FactorPlatelet-Derived Growth Factor ReceptorPositioning AttributePrincipal InvestigatorProtein OverexpressionProtein Tyrosine KinaseProteinsPyrimidinePyrimidinesReceptor Protein-Tyrosine KinasesRoentgen RaysSU 5416SchemeSeriesSideSignal TransductionSolid NeoplasmStandards of Weights and MeasuresStructureStructure-Activity RelationshipTyrosineTyrosine Kinase InhibitorTyrosine Kinase Receptor InhibitionTyrphostin AG 1295Vascular Endothelial Growth Factor Receptor-2Workanalogantitumor agentbasebenzofuranbenzothiophenechemotherapeutic agentcytotoxicdesignin vivoindoleinhibitor/antagonistmelanomamolecular modelingnovelpharmacophoreprogramspyridinepyrimidine analogquinolinereceptorsmall moleculetumor
项目摘要
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.
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。
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Novel 2-amino-4-oxo-5-arylthio-substituted-pyrrolo[2,3-d]pyrimidines as nonclassical antifolate inhibitors of thymidylate synthase.
新型 2-氨基-4-氧代-5-芳硫基取代-吡咯并[2,3-d]嘧啶作为胸苷酸合成酶的非经典抗叶酸抑制剂。
- DOI:10.1016/j.bmcl.2005.03.029
- 发表时间:2005
- 期刊:
- 影响因子:0
- 作者:Gangjee,Aleem;Jain,HiteshkumarD;Kisliuk,RoyL
- 通讯作者:Kisliuk,RoyL
The contribution of a 2-amino group on receptor tyrosine kinase inhibition and antiangiogenic activity in 4-anilinosubstituted pyrrolo[2,3-d]pyrimidines.
- DOI:10.1016/j.bmcl.2010.03.064
- 发表时间:2010-05-15
- 期刊:
- 影响因子:2.7
- 作者:Gangjee, Aleem;Namjoshi, Ojas A.;Ihnat, Michael A.;Buchanan, Aaron
- 通讯作者:Buchanan, Aaron
Design, synthesis and evaluation of 2-amino-4-m-bromoanilino-6-arylmethyl-7H-pyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors and antiangiogenic agents.
- DOI:10.1016/j.bmc.2010.05.049
- 发表时间:2010-07-15
- 期刊:
- 影响因子:3.5
- 作者:Gangjee, Aleem;Zhao, Ying;Raghavan, Sudhir;Ihnat, Michael A.;Disch, Bryan C.
- 通讯作者:Disch, Bryan C.
Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.
- DOI:10.1016/j.bmc.2012.05.068
- 发表时间:2012-07-15
- 期刊:
- 影响因子:3.5
- 作者:Gangjee, Aleem;Zhao, Ying;Ihnat, Michael A.;Thorpe, Jessica E.;Bailey-Downs, Lora C.;Kisliuk, Roy L.
- 通讯作者:Kisliuk, Roy L.
Synthesis and biological activity of 5-chloro-N⁴-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic agents.
- DOI:10.1016/j.bmc.2013.01.040
- 发表时间:2013-04-01
- 期刊:
- 影响因子:3.5
- 作者:Gangjee, Aleem;Zaware, Nilesh;Raghavan, Sudhir;Disch, Bryan C.;Thorpe, Jessica E.;Bastian, Anja;Ihnat, Michael A.
- 通讯作者:Ihnat, Michael A.
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ALEEM GANGJEE其他文献
ALEEM GANGJEE的其他文献
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{{ truncateString('ALEEM GANGJEE', 18)}}的其他基金
Novel Cytoskeletal Stabilizers as Potential Treatments for Limbic Lewy Body Disorders
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