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Directed Evolution of Peptide Inhibitors of Myc-Max Dimerization (PQ18)

Myc-Max 二聚化肽抑制剂的定向进化 (PQ18)

基本信息

批准号：
8534068
负责人：
Robert Neil Eisenman
金额：
$ 17.99万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8534068
关键词：
Affect Affinity Amino Acid Sequence Amino Acid Substitution Amino Acids Apoptosis Attenuated Bacteriophage T7 Bacteriophages Binding Biochemical Biological Biological Assay C-terminal Cell Cycle Progression Cell Differentiation process Cell Proliferation Cell physiology Cellular biology Computer Simulation Coupled DNA Binding DNA Library DNA-Protein Interaction Development Dimerization Down-Regulation E-Box Elements Energy Metabolism Ensure Family Family member Gene Family Gene Targeting Genes Genetic Genetic Transcription Genomics Growth Helix-Turn-Helix Motifs Heterodimerization Human In Vitro Intervention Lead Leucine Zippers Libraries Lymphoma MYC Family Genes Maintenance Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of prostate Maps Max protein Metabolism Methods Modeling Modification Molecular Mutation Nature Neuroblastoma Normal Cell Oncogenic Peptide Sequence Determination Peptides Phenotype Property Protein Biosynthesis Proteins Regulator Genes Relative (related person)Resolution Rhabdomyosarcoma Role Specificity Surface Techniques Technology Testing Therapeutic Transactivation Treatment Efficacy Validation Variant base c-myc Genes cell growth deep sequencing design dimer directed evolution efficacy testing experimental analysis high risk in vivo inhibitor/antagonist malignant breast neoplasm medulloblastoma member neoplastic cell new technology novel peptidomimetics protein protein interaction transcription factor tumor tumor growth tumor progression tumorigenic uptake

项目摘要

DESCRIPTION (provided by applicant): Deregulation of the expression of myc gene family members is required for tumor progression and maintenance, and is associated with many highly aggressive and poorly differentiated human cancers. In some tumors even transient downregulation of Myc results in tumor regression. Myc functions as part of a network of interacting transcription factors each possessing related but distinct domains involved in protein interaction and DNA binding. Through this basic-helix-loop-helix-zipper (bHLHZip) domain, Myc forms highly specific heterodimers with Max. Myc-Max heterodimers bind ~15% of genomic loci, often resulting in transactivation of genes involved in cellular growth, proliferation, metabolism, apoptosis and differentiation. Conversely, Mxd transcription factors competitively bind to Max and repress Myc gene targets, acting as Myc antagonists. Here we propose to employ a newly developed technology to screen a library of ~600,000 variants of the Max zipper domain and identify peptides that will specifically inhibit Myc-Max dimerization, but not Mxd-Max. Because Mxd-Max heterodimers repress genes activated by Myc-Max we predict that disruption of Myc-Max alone will result in inhibition of Myc driven cell proliferation. Peptide inhibitors derived frm our screen will be tested in biochemical assays and tumor cells. Using computational modeling, directed evolution and biological validation, we will assess the molecular and functional mechanisms of inhibition to ensure protein specificity and therapeutic efficacy in reducing levels of activated Myc and attenuating tumor growth

描述（由申请人提供）：myc基因家族成员表达的失调是肿瘤进展和维持所需的，并且与许多高度侵袭性和低分化的人类癌症相关。在一些肿瘤中，甚至Myc的瞬时下调也会导致肿瘤消退。Myc作为相互作用的转录因子网络的一部分发挥作用，每个转录因子具有涉及蛋白质相互作用和DNA结合的相关但不同的结构域。通过这个碱性螺旋环螺旋拉链（bHLHZip）结构域，Myc与Max形成高度特异性的异二聚体。Myc-Max异二聚体结合约15%的基因组位点，通常导致参与细胞生长、增殖、代谢、凋亡和分化。相反，Mxd转录因子竞争性结合Max并抑制Myc基因靶标，充当Myc拮抗剂。在这里，我们建议采用一种新开发的技术来筛选Max拉链结构域的~ 600，000个变体的文库，并鉴定将特异性抑制Myc-Max二聚化而不是Mxd-Max的肽。因为Mxd-Max异二聚体抑制由Myc-Max激活的基因，我们预测单独破坏Myc-Max将导致Myc驱动的细胞增殖的抑制。从我们的筛选中得到的肽抑制剂将在生物化学测定和肿瘤细胞中进行测试。利用计算机建模、定向进化和生物学验证，我们将评估抑制的分子和功能机制，以确保蛋白质特异性和降低激活的Myc水平和减弱肿瘤生长的治疗效果。