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

c-Myc 的抑制：β 肽最大二聚化

• 批准号: 7101025
• 负责人: DOUGLAS S DANIELS
• 金额: $ 5.2万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101025
• 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）：人类蛋白质c-Myc的过度产生或失调导致伯基特淋巴瘤，并可能与乳腺癌、前列腺癌和皮肤癌有关。 c-Myc活性的抑制剂可引起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。 由于它们的蛋白酶抗性和有利的药效学，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的β肽，合成并测试这些分子抑制c-Myc和防止致癌转化的能力。 一种肽设计策略将并入已知驱动螺旋形成并以结构相容的方式呈递c-Myc结合配偶体Max的表位的序列。 第二种策略将涉及从β-肽文库中选择c-Myc结合肽。 这两种策略将通过c-Myc二聚化区域的结构分析来指导和分析。 这项研究将把现有的α-氨基酸肽库的合成和评价方法扩展到β-氨基酸，将β-肽作为一般类别的治疗剂，并可能产生用于c-Myc相关癌症的新型药物。