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）：人类蛋白质 c-Myc 的过量产生或失调会导致伯基特淋巴瘤，并可能与乳腺癌、前列腺癌和皮肤癌有关。 c-Myc 活性抑制剂可引起诱导肿瘤细胞死亡，但已知的 c-Myc 抑制剂都不是有前途的候选药物。 由于其蛋白酶抗性和良好的药效学，β-氨基酸肽有望克服当前 c-Myc 抑制剂的局限性。 我们建议设计针对 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。 一种肽设计策略将结合已知驱动螺旋形成的序列，并以结构兼容的方式呈现 c-Myc 结合伴侣 Max 的表位。 第二种策略涉及从 β-肽库中选择 c-Myc 结合肽。 这两种策略都将以 c-Myc 二聚化区域的结构分析为指导和分析。 这项研究将把现有的 α 氨基酸肽库合成和评估方法扩展到 β 氨基酸，将 β 肽推进为一类通用治疗药物，并有可能产生用于 c-Myc 相关癌症的新型药物。