Novel Delivery Technology for Potential Drugs for Cervical Cancer

描述（由申请人提供）：蛋白酪氨酸磷酸酶（PTP）是一类酶，最近才发现与各种疾病有关，包括癌症、心血管疾病、免疫疾病、感染性疾病、神经疾病和代谢疾病。用特定的小分子靶向这些蛋白质是一个尚待掌握的挑战，特别是因为在体外抑制PTP的大多数已知化合物的膜不透性。因此，显然需要用于递送高效PTP抑制剂的新概念，并且可以证明为普遍适用的方法。牛痘H1相关（VHR）PTP是一种双特异性Erk和Jnk磷酸酶，其缺失导致HeLa癌细胞中的特异性细胞周期停滞，这表明VHR抑制可能是阻止癌细胞生长而对正常细胞无有害影响的有用方法。初步结果表明，VHR是上调在几个宫颈癌细胞系，鳞状上皮内病变，鳞状细胞癌的子宫颈。特异性小分子VHR抑制剂可以将这种磷酸酶作为治疗宫颈癌的一种新的有前途的药物靶点，并可能成为开发治疗这种疾病的药物的起点。与新的和在体外高活性的磺酸铅结构从化学图书馆筛选工作在手，我们将试图克服这些极其有效的VHR抑制剂的固有的不渗透性问题，通过开发一种新的前药递送技术磺酸PTP/VHR抑制剂。我们将合成各种磺酸酯，它们比相应的游离酸更亲脂，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和被细胞酶处理以恢复其生物活性的能力。最后，我们将使用这些化合物并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13，000名妇女患有宫颈癌。该提案的目标是开发一种新技术，用于有效递送靶向一类称为蛋白酪氨酸磷酸酶（PTP）的酶的药物。PTPs最近与许多人类疾病有关，包括癌症、心血管、免疫、传染、神经和代谢疾病。我们关注的特定PTP称为VHR。我们的初步数据清楚地表明，VHR对宫颈癌的发展至关重要。

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.