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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（由申请人提供）：结直肠癌是一种毁灭性疾病，在美国最常诊断的癌症中排名第三，是癌症死亡的第二大原因。转移性结直肠癌的治疗只有渐进的进展，因此存在设计和开发新药的迫切未满足的医疗需求。核心挑战是验证新的药物靶点，并产生破坏这些分子靶点的新疗法。虽然蛋白激酶是最流行的分子癌症靶标之一，但与癌症有关的22种致癌人类蛋白酪氨酸磷酸酶尚未受到适当的关注，并且没有一种具有治疗上有吸引力的抑制剂。磷酸酶显然在癌症中具有非冗余的作用，并且参与对癌基因和治疗的适应性反应。验证蛋白酪氨酸磷酸酶作为结直肠癌的分子靶点，并帮助开发小分子作为治疗结直肠癌的先导，将产生巨大的影响。越来越多的证据表明蛋白酪氨酸磷酸酶4A 3（PTP 4A 3; 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小分子抑制剂相互作用的信息。这项创新的提议汇集了一个经验丰富的多学科团队，他们将使用X射线晶体学来了解小分子抑制剂的相互作用，并利用最近生成的动物模型和细胞来应对这些挑战。如果成功，该提案将产生新的试剂和信息，这将增强我们对PTP 4A 3在癌症生物学中作用的理解，并促进设计和开发全新的抗癌药物。在这种跨学科的方法中，我们提出了两个创新和互补的具体目标。具体目的1：确定小分子配体与PTP 4A 3的相互作用。具体目标2：定义PTP 4A 3的功能作用。