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

这个小型企业创新研究（SBIR）二期项目创造了一种强大的药物发现技术，该技术使用一种创新的基于片段的方法来识别困难靶标的小分子抑制剂。虽然许多多肽可以破坏蛋白质之间的相互作用，但传统的筛选技术很少能成功地识别出具有这种作用的小分子。在这个项目中，通过迭代，系统，经验筛选方法，将肽转化为小分子药物，由此可以进化出小分子来利用基于肽的抑制剂的关键结合特性。这项名为Chemotype Evolution的专利技术将应用于抗癌靶点p53-HDM2。I/IB期研究表明，多肽可以被分解成适合进行化学型进化的诱饵。在第二阶段，Chemotype Evolution将用于将这些基于肽的诱饵转化为新的、有效的、完全非肽的p53-HDM2相互作用抑制剂。此外，通过添加额外的化学物质，该技术的灵活性将得到提高。这项研究的广泛影响是双重的。首先，发现的抑制剂可能会导致治疗癌症的新药。其次，它们的鉴定将验证一种药物发现技术，这种技术可以普遍应用于困难的目标。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，这项技术将推动分子识别领域的发展，并为创建化学探针来研究生物途径提供一种快速和经济有效的方法。社会影响将是巨大的，因为这项技术将促进发现药物，以满足未得到满足的医疗需求，特别是在传统技术失败的地方。

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.