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

• 批准号: 7163018
• 负责人: ALEEM GANGJEE
• 金额: $ 27.86万
• 依托单位: DUQUESNE UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/7163018
• 关键词: Amino Acid Sequence; Angiogenesis Inhibitors; Arts; Benzofurans; Binding; Biological; Biological Assay; Cell Line; Cell Proliferation; Cells; Chemotherapy-Oncologic Procedure; Clinical Trials; Collaborations; Complement component C1s; Cytostatics; Cytotoxic agent; Differentiation and Growth; Dihydrofolate Reductase; Dihydrofolate Reductase Inhibitor; Ear; Endothelial Growth Factors Receptor; Epidermal Growth Factor Receptor; Evaluation; Event; Fibroblast Growth Factor Receptors; Goals; Growth Factor Receptors; H 89; Human; In Vitro; Indoles; Isomerism; Isoquinolines; Lead; Literature; Malignant Neoplasms; Modeling; Mus; Neoplasm Metastasis; Numbers; PD153035; PDGFRB gene; Peptide Sequence Determination; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Positioning Attribute; Principal Investigator; Protein Overexpression; Protein Tyrosine Kinase; Proteins; Pyrimidine; Pyrimidines; Receptor Protein-Tyrosine Kinases; Roentgen Rays; SU 5416; Scheme; Series; Side; Signal Transduction; Solid Neoplasm; Standards of Weights and Measures; Structure; Structure-Activity Relationship; Tyrosine; Tyrosine Kinase Inhibitor; Tyrosine Kinase Receptor Inhibition; Tyrphostin AG 1295; Vascular Endothelial Growth Factor Receptor-2; Work; analog; antitumor agent; base; benzofuran; benzothiophene; chemotherapeutic agent; cytotoxic; design; in vivo; indole; inhibitor/antagonist; melanoma; molecular modeling; novel; pharmacophore; programs; pyridine; pyrimidine analog; quinoline; receptor; small molecule; tumor

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（RTKs）利用ATP自磷酸化序列中的特定酪氨酸残基

项目成果

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: Bioorganic & medicinal chemistry letters.
• 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: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 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: BIOORGANIC & MEDICINAL CHEMISTRY
• 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: BIOORGANIC & MEDICINAL CHEMISTRY
• 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: BIOORGANIC & MEDICINAL CHEMISTRY
• 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.