Drugging the Undruggable: Targeting Transcription Factors with Small Cyclic Pept

描述（由申请人提供） 摘要：Drugging the Undruggable：Myc、STAT 3和HSF 1等转录因子是新型癌症治疗的关键靶点。由于它们缺乏传统药物靶点的结构特征，这些蛋白质通常被归类为“不可用药的”。“这种假设是永久的事实，尽管密集的筛选工作使用传统的方法，有很少的已知化合物靶向转录因子。然而，有效的天然产物，如环孢霉素和雷帕霉素可以结合不同的，非传统的目标，否则会被忽视。环肽类似于这些天然产物大环化合物，因此具有靶向有希望的蛋白质的潜力，包括转录因子，这些蛋白质以前被认为是“不可药用的”。“需要新的筛选技术来发现生物活性环肽（CP）。我们最近描述了一种方法，遗传编码CP库的表型选择在酵母酿酒酵母。由于转录是如此基本的过程，因此在活生物体中进行选择以确保在完整真核转录机制的背景下对靶蛋白的活性和选择性是至关重要的。该技术允许在一天内在活细胞中筛选数千万个CP，而无需昂贵的机器人，并为二次测试和优化命中提供了快速途径。该提案描述了该方法在发现抑制与癌症有关的多种人类转录因子的CP中的应用。这将通过以下方式实现：（1）工程化酵母选择菌株，其报告Myc、STAT 3和HSF 1的蛋白质-蛋白质和蛋白质-DNA相互作用，（2）将CP文库应用于选择菌株以分离选择性地破坏这些相互作用的分子，以及（3）在分子和细胞水平上阐明最有希望的CP的作用机制。这些实验将提供一流的药物线索，适合进一步开发，也将展示一种快速，廉价的方法来发现药物，以前被忽视的目标。 公共卫生相关性：尽管转录因子在疾病生物学中起着重要作用，但由于其结构特性，它们被认为是“不可治疗的”。该提案概述了针对这些蛋白质进行治疗干预的一般策略，并将该策略应用于导致人类癌症的多种转录因子。这些和其他被忽视的药物靶点的验证将是每个主要疾病领域药物开发的真正游戏规则改变者。

DESCRIPTION (Provided by the applicant) Abstract: Drugging the Undruggable: Targeting Transcription Factors with Small Cyclic Peptides Transcription factors such as Myc, STAT3 and HSF1 represent key targets for novel cancer therapies. Because they lack the structural features of traditional drug targets, these proteins are often classified as "undruggable." This assumption is perpetuated by the fact that, despite intensive screening efforts using traditional methods, there are few known compounds that target transcription factors. However, potent natural products such as cyclosporine and rapamycin can bind diverse, non-traditional targets that would otherwise be overlooked. Cyclic peptides resemble these natural product macrocycles, and thus have the potential to target promising proteins, including transcription factors, previously dismissed as "undruggable." Novel screening technologies will be required to discover bioactive cyclic peptides (CPs). We recently described a method of genetically encoding CP libraries for phenotypic selections in the yeast Saccharomyces cerevisiae. Since transcription is such a fundamental process, it is critical to perform selections in live organisms to ensure activity and selectivity for the target protein in the context of the full eukaryotic transcriptional machinery. This technique allows tens of millions of CPs to be screened in live cells in a single day without expensive robotics, and provides a rapid route for secondary testing and optimization of hits. This proposal describes application of this method to discover CPs that inhibit diverse human transcription factors implicated in cancer. This will be accomplished by: (1) engineering yeast selection strains that report on protein-protein and protein-DNA interactions of Myc, STAT3 and HSF1, (2) applying CP libraries to the selection strains to isolate molecules that selectively disrupt these interactions, and (3) elucidating the mechanisms of action of the most promising CPs at the molecular and cellular level. These experiments will provide first-in-class drug leads suitable for further development, and will also demonstrate a rapid, inexpensive approach to drug discovery for previously overlooked targets. Public Health Relevance: Despite their fundamental roles in disease biology, transcription factors have been dismissed as "undruggable" due to their structural properties. This proposal outlines a general strategy for targeting these proteins for therapeutic intervention, and applies this strategy to diverse transcription factors that cause human cancer. Validation of these and other overlooked drug targets would be a true game-changer for drug development in every major disease field.