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（由申请人提供）：蛋白酪氨酸磷酸酶（PTP）是一类最近才与多种疾病相关的酶，包括癌症、心血管、免疫、感染、神经和代谢疾病。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体外抑制 PTP 的化合物具有膜不渗透性。因此，显然需要提供高效 PTP 抑制剂的新概念，并且可以证明是普遍适用的方法。痘苗病毒 H1 相关 (VHR) PTP 是一种双特异性 Erk 和 Jnk 磷酸酶，其缺失会导致 HeLa 癌细胞中特定的细胞周期停滞，这表明 VHR 抑制可能是一种有效的方法，可在不影响细胞生长的情况下阻止癌细胞生长。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上调。 VHR 的特异性小分子抑制剂可以将这种磷酸酶确立为治疗宫颈癌的新型且有前景的药物靶点，并且可能成为开发治疗该疾病的药物的起点。凭借从化学库筛选中获得的新型体外高活性磺酸先导结构，我们将尝试通过开发用于磺酸 PTP/VHR 抑制剂的新前药递送技术来克服这些极其有效的 VHR 抑制剂固有的不渗透性问题。我们将合成各种磺酸酯，它们比相应的游离酸更具亲脂性，因此更容易穿透细胞膜。我们将在体外以及基于细胞的测定中评估这些前药的跨膜能力以及被细胞酶加工以恢复其生物活性的能力。最后，我们将采用这些化合物并在宫颈癌细胞系中进行测试，以证明 VHR 作为治疗宫颈癌的合适药物靶标，仅在美国，宫颈癌每年就会影响 13,000 名女性。该提案的目标是开发一种新技术，用于有效递送针对一类称为蛋白酪氨酸磷酸酶（PTP）的酶的药物。最近，PTP 与许多人类疾病有关，包括癌症、心血管、免疫、传染病、神经和代谢疾病。我们关注的具体 PTP 称为 VHR。我们的初步数据清楚地表明 VHR 对于宫颈癌的发展至关重要。

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：
发表时间：
2009-11-12
期刊：
影响因子：
7.3
作者：
Wu, Shuangding;Vossius, Sofie;Rahmouni, Souad;Miletic, Ana V;Vang, Torkel;Vazquez;Cerignoli, Fabio;Arimura, Yutaka;Williams, Scott;Hayes, Tikva;Moutschen, Michel;Vasile, Stefan;Pellecchia, Maurizio;Mustelin, Tomas;Tautz, Lut
通讯作者：
Tautz, Lut

A highly convergent synthesis of myristoyl-carba(dethia)-coenzyme A.

肉豆蔻酰-卡巴(脱硫)-辅酶 A 的高度收敛合成。