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Novel Delivery Technology for Potential Drugs for Cervical Cancer

宫颈癌潜在药物的新型输送技术

基本信息

批准号：
7554157
负责人：
Lutz Tautz
金额：
$ 21.49万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-09 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7554157
关键词：
Acids Aftercare Amino Acids Binding Biological Biological Assay Cancer Cell Growth Cancer cell line Cardiovascular system Cell Cycle Cell Cycle Arrest Cell Death Cell Membrane Permeability Cell membrane Cell physiology Cells Cervical Squamous Cell Carcinoma Data Development Disease Dose Drug Delivery Systems Elements Enzymes Esters Goals H1-related protein-tyrosine phosphatase Hand Hela Cells Hydrolysis In Vitro Lead Link Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of cervix uteri Measures Membrane Metabolic Diseases Methods Neurologic Normal Cell Pharmaceutical Preparations Phosphoric Monoester Hydrolases Principal Investigator Prodrugs Protein Tyrosine Phosphatase Proteins Screening procedure Squamous intraepithelial lesion Structure Sulfonic Acids Technology Testing Toxic effect Tracer Vaccinia Woman analog base cancer cell human disease inhibitor/antagonist inorganic phosphate keratinocyte new technology novel phosphatase inhibitor process optimization programs small molecule small molecule libraries

项目摘要

DESCRIPTION (provided by applicant): Protein tyrosine phosphatases (PTPs) are a class of enzymes that have just recently been linked to various diseases including cancer, cardiovascular, immunological, infectious, neurological, and metabolic diseases. Targeting these proteins with specific small molecules is a challenge yet to be mastered, in particular because of membrane impermeability of most known compounds that inhibit PTPs in vitro. Thus, new concepts for delivering highly effective PTP inhibitors are clearly needed and could prove as generally applicable methods. The Vaccinia H1-related (VHR) PTP is a dual-specific Erk and Jnk phosphatase, the loss of which causes specific cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells without detrimental effects on normal cells. Preliminary results suggest that VHR is upregulated in several cervix cancer cell lines, in squamous intraepithelial lesions, and squamous cell carcinomas of the uterine cervix. Specific small-molecule inhibitors of VHR could establish this phosphatase as a novel and promising drug target for the treatment of cervical cancer and may be a starting point for developing drugs to treat the disease. With novel and in vitro highly active sulfonic acid lead structures from a chemical library screening effort in hand, we will attempt to overcome the inherent impermeability issues of these extremely effective VHR inhibitors, by developing a new prodrug delivery technology for sulfonic acid PTP/VHR inhibitors. We will synthesize a variety of sulfonic acid esters, which will be more lipophilic than their corresponding free acids and therefore should penetrate cell membranes much more readily. We will evaluate these prodrugs in vitro as well as in cell-based assays for their ability to cross membranes and to be processed by cellular enzymes to regain their biological activity. Finally we will take these compounds and test them in cervix cancer cell lines to prove VHR as a suitable drug target for the treatment of cervical cancer, a disease that effects 13,000 women each year in the US alone. The goal of this proposal is to develop a new technology for effective delivery of drugs targeting a class of enzymes called protein tyrosine phosphatases (PTPs). PTPs have been recently implicated with numerous human diseases, including cancer, cardiovascular, immunological, infectious, neurological, and metabolic diseases. The specific PTP we are focusing on is called VHR. Our preliminary data clearly suggest that VHR is critical for the development of cervical cancer.

描述(申请人提供)：蛋白质酪氨酸磷酸酶(PTPs)是一类酶，最近才被发现与多种疾病有关，包括癌症、心血管疾病、免疫学疾病、传染性疾病、神经系统疾病和代谢性疾病。用特定的小分子靶向这些蛋白质是一个尚未掌握的挑战，特别是因为大多数已知的化合物在体外抑制PTPs的膜不通透性。因此，提供高效PTP抑制剂的新概念显然是必要的，并可能被证明是普遍适用的方法。痘苗病毒H1相关蛋白(VHR)PTP是一种双特异性ERK和JNK磷酸酶，它的缺失会导致HeLa癌细胞特异性的细胞周期停滞，提示抑制VHR可能是一种有效的方法来阻止癌细胞的生长，而不会对正常细胞产生不利影响。初步结果表明，VHR在几种宫颈癌细胞系、鳞状上皮内病变和宫颈鳞状细胞癌中表达上调。VHR的特异性小分子抑制剂可能使这种磷酸酶成为治疗宫颈癌的新的、有前途的药物靶点，并可能成为开发治疗该疾病的药物的起点。随着从化学文库中筛选出新型和体外高活性的磺酸先导结构的努力，我们将试图通过开发一种新的磺酸PTP/VHR抑制剂的前药给药技术，来克服这些极其有效的VHR抑制剂固有的不通透性问题。我们将合成各种磺酸酯，它们比相应的游离酸更亲油，因此应该更容易穿透细胞膜。我们将在体外和基于细胞的分析中评估这些前药的跨膜能力，并被细胞酶处理以恢复其生物活性。最后，我们将用这些化合物在宫颈癌细胞系中进行测试，以证明VHR是治疗宫颈癌的合适药物靶点。仅在美国，每年就有1.3万名女性患上宫颈癌。这项提案的目标是开发一种新的技术，用于有效地输送针对一种名为蛋白质酪氨酸磷酸酶(PTPs)的酶的药物。PTPs最近与许多人类疾病有关，包括癌症、心血管疾病、免疫学疾病、传染性疾病、神经系统疾病和代谢性疾病。我们关注的特定PTP称为VHR。我们的初步数据清楚地表明，VHR在宫颈癌的发展中起着关键作用。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.

痘苗 H1 相关 (VHR) 磷酸酶的多齿小分子抑制剂可减少宫颈癌细胞的增殖。

DOI：
10.1021/jm901016k
发表时间：
2009
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Wu,Shuangding;Vossius,Sofie;Rahmouni,Souad;Miletic,AnaV;Vang,Torkel;Vazquez-Rodriguez,Jesus;Cerignoli,Fabio;Arimura,Yutaka;Williams,Scott;Hayes,Tikva;Moutschen,Michel;Vasile,Stefan;Pellecchia,Maurizio;Mustelin,Tomas;Tautz,Lut
通讯作者：
Tautz,Lut

Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy.