PTP4A3 as a Molecular Cancer Target

PTP4A3 作为分子癌症靶点

基本信息

批准号：
8814295
负责人：
JOHN S. LAZO
金额：
$ 20.42万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-19 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8814295
关键词：
Address Animal Model Antineoplastic Agents Attention Binding Binding Proteins Breast C-terminal Cancer Biology Cancer Etiology Cells Cessation of life Colonic Neoplasms Colorectal Colorectal Cancer Crystallography Cytokeratin 8 Development Diagnosis Disease Drug Targeting Endothelial Cells Endothelium Family member Foundations Funding Funding Opportunities Future Gene Family Generations Goals Grant Human In Vitro Knowledge Label Lead Ligands Link Liver Malignant Neoplasms Medical Membrane Messenger RNA Modeling Molecular Molecular Target Mus Neoplasm Metastasis Nodal Oncogenes Oncogenic Ovary PTP4A2 gene Partial Hepatectomy Pathway interactions Pharmaceutical Preparations Phosphatidylinositols Phosphoric Monoester Hydrolases Protein Dephosphorylation Protein Kinase Protein Tyrosine Phosphatase Proteins Reagent Reporting Research Proposals Role Second Primary Cancers Signal Pathway Signal Transduction Stomach Structure Testing Therapeutic Transforming Growth Factors Tube Tumor Cell Invasion Validation Vascular Endothelial Growth Factors cancer diagnosis cancer therapy design drug development drug discovery experience ezrin inhibitor/antagonist innovation interdisciplinary approach interest intestinal epithelium member metastatic colorectal migration mouse model multidisciplinary novel novel strategies novel therapeutics nucleolin outcome forecast overexpression phosphatase of regenerating liver prenylation public health relevance response rho GTP-Binding Proteins small molecule stathmin tool development tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer is a devastating disease, ranking as the third most commonly diagnosed US cancer and second leading cause of cancer death. There have been only incremental advancements in the treatment of metastatic colorectal cancer so an urgent unmet medical need exists to design and develop new drugs. The central challenge has been to validate novel drug targets and to generate new therapies that disrupt these molecular targets. While protein kinases are among the most popular molecular cancer targets, the 22 oncogenic human protein tyrosine phosphatases that are implicated in cancer have not received suitable attention and none have therapeutically attractive inhibitors. Phosphatases clearly have a non-redundant role in cancer as well as participate in adaptive responses to oncogenes and therapies. Validating a protein tyrosine phosphatase as a molecular target for colorectal cancer and helping to develop small molecules as leads for the treatment of colorectal cancer would have an enormous impact. There is growing evidence that Protein Tyrosine Phosphatase 4A3 (PTP4A3; a/k/a PRL-3) is involved in cancer progression and metastasis. Further target validation and information about small molecule inhibitor interactions are needed. This innovative proposal brings together an experienced multidisciplinary team that will use x-ray crystallography to understand small molecule inhibitor interactions and exploit a recently generated animal model and cells to address these challenges. If successful, this proposal will generate new reagents and information that will enhance our understanding of the role of PTP4A3 in cancer biology and facilitate the design and development of an entirely new class of anticancer agents. In this interdisciplinary approach, we propose two innovative and complementary Specific Aims. Specific Aim 1: Determining the interactions of small molecule ligands with PTP4A3. Specific Aim 2: Define the functional role of PTP4A3.

描述（由适用提供）：结直肠癌是一种毁灭性的疾病，被评为第三个通常被诊断出的美国癌症和癌症死亡的第二大原因。在治疗转移性结直肠癌的治疗方面仅取得了不断的进步，因此存在紧急的未满足医疗需求以设计和开发新药。核心挑战是验证新型药物靶标并产生破坏这些分子靶标的新疗法。虽然蛋白激酶是最流行的分子癌靶标之一，但在癌症中隐含的22种致癌性人蛋白酪氨酸磷酸酶尚未受到适当的注意，也没有任何治疗性抑制剂。磷酸酶显然在癌症中具有非冗余作用，并参与对癌基因和疗法的适应性反应。验证蛋白质酪氨酸磷酸酶是结直肠癌的分子靶标，并有助于开发小分子作为治疗结直肠癌的铅，将产生增强的影响。越来越多的证据表明蛋白酪氨酸磷酸酶4A3（PTP4A3； A/K/A PRL-3）参与癌症进展和转移。需要进一步的目标验证和有关小分子抑制剂相互作用的信息。这项创新的建议汇集了一个经验丰富的多学科团队，该团队将使用X射线晶体学来了解小分子抑制剂相互作用，并探索最近生成的动物模型和细胞以应对这些挑战。如果成功，该提案将产生新的试剂和信息，从而增强我们对PTP4A3在癌症生物学中的作用的理解，并支持全新的抗癌药物的设计和开发。在这种跨学科的方法中，我们提出了两个创新且完全具体的目标。具体目标1：确定小分子配体与PTP4A3的相互作用。特定目标2：定义PTP4A3的功能作用。