Targeting Glioblastoma Using Novel Small Molecule HIF-1 Pathway Inhibitors

使用新型小分子 HIF-1 通路抑制剂靶向胶质母细胞瘤

基本信息

批准号：
8119393
负责人：
ERWIN G VAN MEIR
金额：
$ 42.78万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8119393
关键词：
Adjuvant Radiotherapy Affect Angiogenic Factor Animal Cancer Model Animal Disease Models Animal Model Anoxia Apoptotic Area Astrocytoma Behavior Benzopyrans Biodistribution Biological Assay Biological Factors Biological Models Blood - brain barrier anatomy Cancer Patient Cell Culture Techniques Cell Fraction Cells Characteristics Chemical Structure Clinical Treatment Clinical Trials Comparative Study Data Development Drug Kinetics Effectiveness Electrodes Environment Enzymes Evaluation Experimental Models Gene Targeting Genetic Genetic Transcription Glioblastoma Glioma Goals Growth Health Human Hypoxia Image Immunohistochemistry In Vitro Injection of therapeutic agent Knock-out LacZ Genes Lead Libraries Luciferases Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Measurement Mediating Messenger RNA Metabolic Metabolism Modeling Molecular Molecular Target Mus National Cancer Institute Necrosis Neoplasm Metastasis Nuclear Oxygen Pathway interactions Patients Permeability Pharmaceutical Preparations Pharmacodynamics Physiological Pimonidazole Polyribosomes Post-Translational Protein Processing Property Protein Inhibition Proteins Radiation therapy Radio Radiolabeled Rattus Reporter Reporter Genes Research Personnel Resistance Rodent Safety Screening procedure Signal Pathway Signal Transduction Solid Neoplasm Specificity Staining method Stains Structure Structure-Activity Relationship Systems Biology Testing Therapeutic Therapeutic Agents Time Tissues Toxicology Translating Translations Tumor Angiogenesis Vascularization Xenograft procedure angiogenesis base cancer cell cancer therapy cancer type cellular targeting chemotherapeutic agent chemotherapy combinatorial design effective therapy environmental change expectation improved in vitro activity in vivo inhibitor/antagonist innovation luminescence neoplastic cell novel novel strategies overexpression preclinical study pressure programs radiotracer response small molecule transcription factor tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): There is an urgent need to develop novel therapies for malignant solid tumors. Tumor hypoxia, a reduction In partial oxygen pressure is a characteristic of solid tumor growth and develops following insufficient oxygen supply from preexisting vasculature. This phenomenon stimulates tumor progression by activating physiological responses that permit tumor-induced angiogenesis and metabolic adaptation to growth under a hypoxic environment. It is also a major factor in the resistance of cancer cells to radio- and chemo-therapies. Hypoxia triggers activation of Hypoxia-lnducible Factor 1 (HIF-1), a transcription factor that drives transcription of genes encoding pro-angiogenic factors and glycolytic enzymes that contribute to tumor growth. Strategies that inhibit HIF-1 function through HIF-?? knockdown or knockout approaches have reduced tumor growth in experimental models including glioblastoma, the most malignant brain tumor for which there is currently no effective therapy. Here we would like to test the hypothesis that small molecules that inhibit the HIF-1 pathway will inhibit the growth of glioblastoma, either singly or in combination with other agents. We have developed a novel pipeline of such potential therapeutic agents by screening a natural product-like library of small molecular compounds using a HIF-1-responsive cell-based reporter assay. We have generated extensive preliminary data showing that two structural classes of compounds identified have potent anti-HIF activity in vitro and in vivo. Furthermore, we have found that our lead HIF inhibitor acts via a unique mechanism and is able to strongly inhibit in vivo tumor growth upon systemic administration. Here we plan to further develop these lead molecules, test them further in animal models of glioblastoma as a model for an aggressive solid tumor relying on HIF-1 activation for its growth, and determine their precise mechanism of action. These studies are innovative in that these molecules have a novel unique chemical structure and mechanism of action, and there is a pressing need for small molecule HIF pathway inhibitors. These small molecules have great potential as candidate therapeutics for a large number of solid tumors that rely on the HIF pathway for their growth. These preclinical studies have the potential to directly benefit human health by increasing the survival of cancer patients, a main goal of the National Cancer Institute.

描述（由申请人提供）：迫切需要开发针对恶性实体瘤的新疗法。肿瘤缺氧，部分氧气压力的降低是实体肿瘤生长的特征，并且在先前存在的脉管系统中氧供应不足之后发展。这种现象通过激活生理反应刺激肿瘤进展，从而使肿瘤诱导的血管生成和对低氧环境下生长的代谢适应性。它也是癌细胞对放射性和化学治疗的抗性的主要因素。缺氧会触发低氧可耐受性因子1（HIF-1）的激活，这是一种驱动编码促血管生成因子和糖酵解酶的基因转录的转录因子，这些酶有助于肿瘤的生长。通过HIF-？抑制HIF-1功能的策略 - 在包括胶质母细胞瘤在内的实验模型中，敲低或敲除方法降低了肿瘤的生长，这是目前尚无有效治疗的最恶性脑肿瘤。在这里，我们想检验以下假设：抑制HIF-1途径的小分子将抑制胶质母细胞瘤的生长，无论是单独或与其他药物的结合。我们通过使用基于HIF-1反应性细胞的记者测定法筛选出类似于小分子化合物的天然产物样库，从而开发了这种潜在治疗剂的新型管道。我们已经产生了广泛的初步数据，表明所鉴定的两个结构性类别在体外和体内具有有效的抗HIF活性。此外，我们发现我们的铅HIF抑制剂通过独特的机制起作用，并且能够在全身给药时强烈抑制体内肿瘤的生长。在这里，我们计划进一步开发这些铅分子，在胶质母细胞瘤的动物模型中进一步测试它们，作为依靠HIF-1激活其生长的攻击性实质性瘤的模型，并确定其精确的作用机理。这些研究具有创新性，因为这些分子具有新颖的独特化学结构和作用机理，并且对小分子HIF途径抑制剂的需求紧迫。这些小分子作为依靠HIF途径生长的大量实体瘤的候选疗法具有很大的潜力。这些临床前研究有可能通过增加癌症患者的生存，这是国家癌症研究所的主要目标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Examining the structure-activity relationship of benzopyran-based inhibitors of the hypoxia inducible factor-1 pathway.

DOI：
10.1016/j.bmcl.2017.02.073
发表时间：
2017-04-15
期刊：
Bioorganic & medicinal chemistry letters
影响因子：
2.7
作者：
Ferguson J;De Los Santos Z;Devi N;Van Meir E;Zingales S;Wang B
通讯作者：
Wang B

Design and in vitro activities of N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, novel, small-molecule hypoxia inducible factor-1 pathway inhibitors and anticancer agents.

DOI：
10.1021/jm300752n
发表时间：
2012-08-09
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Mun, Jiyoung;Jabbar, Adnan Abdul;Devi, Narra Sarojini;Yin, Shaoman;Wang, Yingzhe;Tan, Chalet;Culver, Deborah;Snyder, James P.;Van Meir, Erwin G.;Goodman, Mark M.
通讯作者：
Goodman, Mark M.

Hypoxia inducible factor pathway inhibitors as anticancer therapeutics.

DOI：
10.4155/fmc.13.17
发表时间：
2013-04
期刊：
Future medicinal chemistry
影响因子：
4.2
作者：
Burroughs SK;Kaluz S;Wang D;Wang K;Van Meir EG;Wang B
通讯作者：
Wang B

Biology of advanced uveal melanoma and next steps for clinical therapeutics.

DOI：
10.1111/pcmr.12304
发表时间：
2015-03
期刊：
Pigment cell & melanoma research
影响因子：
4.3
作者：
Luke JJ;Triozzi PL;McKenna KC;Van Meir EG;Gershenwald JE;Bastian BC;Gutkind JS;Bowcock AM;Streicher HZ;Patel PM;Sato T;Sossman JA;Sznol M;Welch J;Thurin M;Selig S;Flaherty KT;Carvajal RD
通讯作者：
Carvajal RD

Design and synthesis of novel small-molecule inhibitors of the hypoxia inducible factor pathway.

DOI：
10.1021/jm201018g
发表时间：
2011-12-22
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Mooring, Suazette Reid;Jin, Hui;Devi, Narra S.;Jabbar, Adnan A.;Kaluz, Stefan;Liu, Yuan;Van Meir, Erwin G.;Wang, Binghe
通讯作者：
Wang, Binghe