SBIR Phase II: A new drug discovery method to transform peptides to small molecules: proof of principle with p53-hdm2

SBIR II 期：一种将肽转化为小分子的新药物发现方法：用 p53-hdm2 进行原理证明

• 批准号: 1127154
• 负责人: Daniel Erlanson
• 金额: $ 50万
• 依托单位: Carmot Therapeutics, Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1127154&HistoricalAwards=false
• 关键词: SBIR; Phase; II; new; drug

This Small Business Innovation Research (SBIR) Phase II project creates a powerful drug discovery technology that uses an innovative fragment-based approach to identify small molecule inhibitors of difficult targets. Though many peptides can disrupt protein-protein interactions, conventional screening technologies are rarely successful at identifying small molecules that do so. In this project peptides are transformed into smallmolecule drugs through an iterative, systematic, empirical screening approach, whereby a small molecule can be evolved to harness key binding properties of peptide-based inhibitors. This proprietary technology, Chemotype Evolution, will be applied to the anticancer target p53-HDM2. The Phase I/IB grant demonstrated that peptides can be deconstructed into baits suitable for performing Chemotype Evolution. In Phase II, Chemotype Evolution will be used to convert these peptide-based baits into novel, potent, completely non-peptidic inhibitors of the p53-HDM2 interaction. Moreover, the flexibility of the technology will be increased by adding additional chemistries.The broader impacts of this research are two-fold. First, the inhibitors discovered could lead to new drugs for treating cancer. Second, their identification will validate a drug discovery technology that can be applied generally to difficult targets. Routine transformation of peptides into small-molecule drugs would create a wealth of profitable opportunities. Scientifically, this technology will advance the field of molecular recognition and provide a rapid and cost effective method for creating chemical probes to investigate biological pathways. The societal impact will be substantial, as the technology will facilitate the discovery of drugs for unmet medical needs, particularly where conventional technologies have failed.

这个小企业创新研究（SBIR）第二阶段项目创建了一个强大的药物发现技术，该技术使用一种基于片段的创新方法来识别困难靶点的小分子抑制剂。虽然许多肽可以破坏蛋白质-蛋白质相互作用，但传统的筛选技术很少成功地识别这样做的小分子。在该项目中，肽通过迭代，系统，经验筛选方法转化为小分子药物，从而可以进化小分子以利用基于肽的抑制剂的关键结合特性。这项专利技术，Chemotype Evolution，将应用于抗癌靶点p53-HDM 2。I/IB期资助证明，肽可以被解构成适合进行化学型进化的诱饵。在第二阶段，化学型进化将用于将这些基于肽的诱饵转化为p53-HDM 2相互作用的新型、有效、完全非肽抑制剂。此外，该技术的灵活性将通过添加额外的化学物质来增加。首先，发现的抑制剂可能导致治疗癌症的新药。其次，它们的鉴定将验证一种可普遍应用于困难靶点的药物发现技术。将多肽常规转化为小分子药物将创造大量有利可图的机会。从科学上讲，这项技术将推进分子识别领域，并为创建化学探针以研究生物途径提供快速且具有成本效益的方法。社会影响将是巨大的，因为该技术将有助于发现满足未满足医疗需求的药物，特别是在传统技术失败的情况下。