更新于：2024-11-01

EGFR x VEGFR2 x Tubulin x PDGFRβ

更新于：2024-11-01

基本信息

关联

项与 EGFR x VEGFR2 x Tubulin x PDGFRβ 相关的药物

AG-321

靶点

EGFR x PDGFRβ x Tubulin x VEGFR2

作用机制

EGFR拮抗剂 [+3]

在研机构-

原研机构

Duquesne University of The Holy Spirit

在研适应症-

非在研适应症

肿瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 EGFR x VEGFR2 x Tubulin x PDGFRβ 相关的临床结果

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100 项与 EGFR x VEGFR2 x Tubulin x PDGFRβ 相关的转化医学

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0 项与 EGFR x VEGFR2 x Tubulin x PDGFRβ 相关的专利（医药）

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项与 EGFR x VEGFR2 x Tubulin x PDGFRβ 相关的文献（医药）

2017-01-01·Bioorganic & Medicinal Chemistry3区 · 医学

Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents

3区 · 医学

Article

作者: Pavana, Roheeth Kumar ; Ihnat, Michael A ; Bai, Ruoli ; Choudhary, Shruti ; Bastian, Anja ; Hamel, Ernest ; Gangjee, Aleem

The utility of cytostatic antiangiogenic agents (AA) in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of AA with microtubule targeting agents (MTAs) have been particularly successful. The discovery, synthesis and biological evaluations of a series of 7-benzyl-N-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds which inhibit proangiogenic receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR), along with microtubule targeting in single molecules are described. These compounds also inhibited blood vessel formation in the chicken chorioallantoic membrane (CAM) assay, and some potently inhibited tubulin assembly (with activity comparable to that of combretastatin A-4 (CA)). In addition, some of the analogs circumvent the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to microtubule targeting agents (MTA). These MTAs bind at the colchicine site on tubulin. Two analogs displayed two to three digit nanomolar GI₅₀ values across the entire NCI 60 tumor cell panel and one of these, compound 7, freely water soluble as its HCl salt, afforded excellent in vivo antitumor activity against an orthotopic triple negative 4T1 breast cancer model and was superior to doxorubicin.

2016-01-01·American journal of translational research

Tumor profiling of co-regulated receptor tyrosine kinase and chemoresistant genes reveal different targeting options for lung and gastroesophageal cancers.

Article

作者: Sharma, Ashok ; Cao, Haixia ; Ma, Rong ; Bai, Shan ; Jing, Changwen ; Wu, Jianzhong ; Li, Shuchun ; Feng, Jifeng ; Dun, Boying ; She, Jinxiong

The expression of a number of genes can influence the response rates to chemotherapy while genes encoding receptor tyrosine kinases (RTKs) determine the response to most targeted cancer therapies currently used in clinics. In this study, we evaluated seven genes known to influence chemotherapeutic response (ERCC1, BRCA1, RRM1, TUBB3, STMN1, TYMS, and TOP2A) and five RTKs (EGFR, ERBB2, PDGFRB, VEGFR1 and VEGFR2) in non-small cell lung cancer (NSCLC) and esophagus cancer (EC) and the data are compared to gastric cancer (GC) data reported previously. We demonstrate significant differences in the expression profiles between different cancer types as well as heterogeneity among patients within the same cancer type. In all three cancer types, five chemoresistant genes (TOP2A, STMN1, TYMS, BRCA1 and RRM1) are coordinately up-regulated in almost all EC, approximately 90% of NSCLC and one third of GC patients. Most EC and nearly half of GC patients have increased expression of the three RTKs critical to angiogenesis (PDGFR, VEGFR1 and VEGFR2), while almost none of the NSCLC patients have elevated expression of angiogenic RTKs. A variable percentage of patients in the three cancer types show upregulation of the EGFR family RTKs, EGFR and/or ERBB2. It is of interest to note that approximately 10% of the NSCLC and GC patients are triple-negative for the chemosensitivity genes, angiogenic and EGFR RTK genes. The results suggest significant gene expression differences between different cancer types as well as heterogeneity within each cancer type and therefore different molecules should be targeted for future drug development and clinical trials.

2015-05-01·Bioorganic & Medicinal Chemistry3区 · 医学

The design, synthesis and biological evaluation of conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multi-targeted receptor tyrosine kinase and microtubule inhibitors as potential antitumor agents

3区 · 医学

Article

作者: Hamel, Ernest ; Bastian, Anja ; Raghavan, Sudhir ; Zhang, Xin ; Ihnat, Michael ; Mooberry, Susan L ; Zammiello, Cynthia ; Gangjee, Aleem

A series of eleven conformationally restricted, 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines was designed to explore the bioactive conformation required for dual inhibition of microtubule assembly and receptor tyrosine kinases (RTKs), and their biological activities are reported. All three rotatable single bonds in the lead compound 1 were sequentially restricted to address the role of each in SAR for microtubule and RTK inhibitory effects. Compounds 2, 3, 7 and 10 showed microtubule depolymerizing activity comparable to or better than the lead 1, some with nanomolar EC50 values. While compound 8 had no effect on microtubules, 8 and 10 both showed potent RTK inhibition with nanomolar IC50s. These compounds confirm that the bioactive conformation for RTK inhibition is different from that for tubulin inhibition. The tetrahydroquinoline analog 10 showed the most potent dual tubulin and RTK inhibitory activities (low nanomolar inhibition of EGFR, VEGFR2 and PDGFR-β). Compound 10 has highly potent activity against many NCI cancer cell lines, including several chemo-resistant cell lines, and could serve as a lead for further preclinical studies.