Focal Adhesion Kinase - Tumor Biology and Therapeutics

粘着斑激酶 - 肿瘤生物学和治疗学

基本信息

批准号：
10366214
负责人：
Timothy A Marlowe
金额：
$ 33.82万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-30 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366214
关键词：
3-Dimensional Adhesions Aftercare Antineoplastic Agents Apoptosis BRAF gene Binding Biological Biological Assay Cell Line Cell Survival Cell model Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Complex Crystallization Crystallography Data Dependence Development Drug Kinetics Drug Targeting Engineering Enzymes Evaluation Extracellular Matrix Focal Adhesion Kinase 1 Focal Adhesions Funding Genes Genetic Immune Cell Suppression In Vitro Lead Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Melanoma Cell Molecular Monitor Mutation Neoplasm Metastasis Normal tissue morphology Oncology Outcome Pathway interactions Patients Peptides Permeability Pharmaceutical Preparations Phase I/II Clinical Trial Phosphotransferases Progress Reports Property Protein Tyrosine Kinase Proteins Proteomics Proto-Oncogene Proteins c-akt Ras/Raf Regulation Research Resistance Rivers Roentgen Rays Role Scaffolding Protein Series Signal Pathway Signal Transduction Skin Cancer Solid Neoplasm Talin Techniques Tertiary Protein Structure Testing Therapeutic Tumor Biology angiogenesis anti-cancer base cancer cell cancer subtypes cell motility improved in vivo inhibitor inhibitor therapy kinase inhibitor melanoma migration mouse model mutant nanomolar novel overexpression patient derived xenograft model paxillin protein complex response scaffold stapled peptide targeted treatment tumor tumor progression tumor xenograft

项目摘要

PROJECT ABSTRACT Focal Adhesion Kinase (FAK) is a multifunctional non-receptor tyrosine kinase and scaffolding protein that is overexpressed in numerous solid tumors including melanoma, while minimally expressed in normal tissue. FAK has been widely investigated as a cancer drug target due its contribution in multiple aspects of tumor progression, including adhesion, invasion, proliferation, survival, metastasis, angiogenesis, and immune cell suppression. However, development of FAK inhibitors has largely focused on inhibition of the kinase enzyme of FAK opposed to inhibition of key scaffolding interactions. Particularly, limited efforts have been made at the discovery and biological evaluation of inhibitors of the focal adhesion targeting (FAT) scaffolding domain of FAK, the domain required for FAK localization to focal adhesions. During this period of support, we have identified the first discovered stapled peptide-based FAK inhibitor (UA-1907) that binds to and co-crystallizes with the FAT domain, and competitively inhibits FAK-paxillin binding. We have identified a myristoylated derivative (UA-2012) with improved cellular potency, favorable drug-like properties, and in vivo efficacy; and developed a bivalent peptide (UA-2023) with low nanomolar binding to FAT. However, the mechanistic differences between these novel FAT domain peptides and traditional FAK-kinase inhibitors on perturbation of focal adhesion complexes and the FAK interactome have yet to be elucidated. Furthermore, we have preliminary data showing that FAT inhibition provides selective anti-cancer effects in NRAS mutant melanoma cells. Melanoma is the deadliest form of skin cancer and there are no current effective targeted therapies against NRAS mutant melanoma, which represents ~30% of all patients. We hypothesize that FAK FAT domain inhibitors have distinct biological effects on the focal adhesion complex in cancer cells compared to FAK kinase inhibitors; and cancer cells with alterations in NRAS signaling pathways have a molecular dependence on FAK FAT scaffolding for survival, thus promoting selective anti-cancer efficacy. In specific aim 1, we will identify the unique differences between FAK FAT scaffold inhibitors and FAK kinase inhibitors on modulation of the focal adhesion complex and the FAK interactome. In specific aim 2, we will define the molecular mechanisms of sensitivity/resistance to FAK FAT inhibition in melanoma cells with activating mutations in NRAS and BRAF pathways. In specific aim 3, we will evaluate in vivo efficacy of novel FAK FAT domain inhibitors in mouse models of NRAS and BRAF driven cancer. Overall, in this project we will utilize FAT stapled peptides to validate that FAT domain targeting provides additional biological efficacy on the focal adhesion complex compared to FAK- kinase inhibitors and that NRAS mutant melanoma has a unique sensitivity to FAK FAT inhibition. .

项目摘要粘着斑激酶 (FAK) 是一种多功能非受体酪氨酸激酶和支架蛋白，在包括黑色素瘤在内的许多实体瘤中过度表达，而在正常组织中最低表达。 FAK 由于其在肿瘤进展的多个方面的贡献，已作为癌症药物靶点被广泛研究，包括粘附、侵袭、增殖、存活、转移、血管生成和免疫细胞抑制。然而，FAK抑制剂的开发主要集中在抑制FAK的激酶上抑制关键支架相互作用。特别是，在发现和 FAK 的粘着斑靶向 (FAT) 支架结构域抑制剂的生物学评价，该结构域 FAK 定位至粘着斑所需。在此支持期间，我们确定了第一个发现了基于钉合肽的 FAK 抑制剂 (UA-1907)，它与 FAT 结构域结合并共结晶，并竞争性抑制 FAK-paxillin 结合。我们已经鉴定出一种肉豆蔻酰化衍生物 (UA-2012) 提高细胞效力、有利的药物样特性和体内功效；并开发了二价肽 (UA-2023) 与 FAT 的纳摩尔结合力较低。然而，这些新型 FAT 之间的机制差异结构域肽和传统 FAK 激酶抑制剂对粘着斑复合物和 FAK 的干扰相互作用组尚未阐明。此外，我们有初步数据表明 FAT 抑制在 NRAS 突变黑色素瘤细胞中提供选择性抗癌作用。黑色素瘤是最致命的皮肤病目前尚无针对 NRAS 突变黑色素瘤的有效靶向治疗方法，这代表约占所有患者的 30%。我们假设 FAK FAT 结构域抑制剂对与 FAK 激酶抑制剂相比，癌细胞中的粘着斑复合物；和癌细胞 NRAS 信号通路的改变对 FAK FAT 支架具有分子依赖性生存，从而促进选择性抗癌功效。在具体目标 1 中，我们将确定独特的 FAK FAT支架抑制剂和FAK激酶抑制剂在调节粘着斑方面的差异复合体和 FAK 相互作用组。在具体目标2中，我们将定义以下分子机制：具有 NRAS 和 BRAF 激活突变的黑色素瘤细胞对 FAK FAT 抑制的敏感性/耐药性途径。在具体目标 3 中，我们将评估新型 FAK FAT 结构域抑制剂在小鼠模型中的体内功效 NRAS 和 BRAF 驱动的癌症。总的来说，在这个项目中，我们将利用 FAT 钉合肽来验证与 FAK- 相比，FAT 结构域靶向对粘着斑复合物提供了额外的生物学功效激酶抑制剂，并且 NRAS 突变黑色素瘤对 FAK FAT 抑制具有独特的敏感性。。