Inhibition of c-Myc: Max dimerization by beta-peptides

c-Myc 的抑制：β 肽最大二聚化

• 批准号: 6994955
• 负责人: DOUGLAS S DANIELS
• 金额: $ 4.99万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6994955
• 关键词: Burkitt' s lymphoma; antineoplastics; breast neoplasms; chemoprevention; drug design /synthesis /production; drug screening /evaluation; gene expression; gene induction /repression; neoplasm /cancer genetics; neoplastic transformation; peptide library; peptides; pharmacokinetics; postdoctoral investigator; prostate neoplasms; protein binding; protein structure function; protooncogene; skin neoplasms; tissue /cell culture

DESCRIPTION (provided by applicant): Overproduction or deregulation of the human protein c-Myc causes Burkitt's lymphoma and may be involved in breast, prostate and skin cancers. Inhibitors of c-Myc activity can cause induced tumor cell death, but none of the known c-Myc inhibitors are promising drug candidates. Due to their protease resistance and favorable pharmacodynamics, peptides of beta-amino acids are poised to overcome limitations of current c-Myc inhibitors. We propose to design beta peptides that target c-Myc, synthesize, and test these molecules for their ability to inhibit c-Myc and prevent the oncogenic transformation. One peptide design strategy will incorporate sequences known to drive helical formation and to present the epitope of the c-Myc binding partner Max in a structurally compatible fashion. A second strategy will involve selection of c-Myc binding peptides from a library of beta-peptides. Both strategies will be guided and analyzed by structural analysis of the c-Myc dimerization region. This research will extend existing methodologies for synthesis and evaluation of alpha-amino acid peptide libraries to beta-amino acids, advance beta-peptides as a general class of therapeutics and potentially generate novel agents for c-Myc related cancers.

描述（由申请人提供）：人蛋白C-MYC的生产过多或失调会导致Burkitt的淋巴瘤，并可能参与乳腺癌，前列腺和皮肤癌。 C-MYC活性的抑制剂会导致诱导的肿瘤细胞死亡，但已知的C-MYC抑制剂都不是有希望的候选药物。 由于其蛋白酶耐药性和有利的药效学，β-氨基酸的肽有望克服当前C-Myc抑制剂的局限性。 我们建议设计靶向C-MYC，合成和测试这些分子抑制C-MYC并防止致癌转化的能力的β肽。 一种肽设计策略将结合已知的序列，以驱动螺旋形成，并以结构兼容的方式呈现C-MYC结合伴侣Max的表位。 第二种策略将涉及从β肽库中选择C-MYC结合肽。 通过对C-Myc二聚体区域的结构分析来指导和分析这两种策略。 这项研究将扩展现有的方法论，用于合成和评估α-氨基酸肽库，以β-氨基酸为β-氨基酸，将β-肽作为一般治疗剂类别，并可能为C-MYC相关的相关癌症产生新的药物。