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

描述（由申请人提供）：人类蛋白c-Myc的过量生产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的肿瘤细胞死亡，但没有一种已知的c-Myc抑制剂是有希望的候选药物。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。一种肽设计策略将包含已知的驱动螺旋形成的序列，并以结构相容的方式呈现c-Myc结合伙伴Max的表位。第二种策略将涉及从β肽库中选择c-Myc结合肽。这两种策略都将通过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合成和评价α -氨基酸肽库的方法扩展到β -氨基酸，将β -肽作为一种一般的治疗方法，并有可能为c-Myc相关癌症产生新的药物。

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.