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)第二阶段项目创造了一种强大的药物发现技术，该技术使用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成功地识别出这样做的小分子。在这个项目中，通过迭代的、系统的、经验的筛选方法将多肽转化为小分子药物，由此可以进化出小分子来利用基于多肽的抑制剂的关键结合特性。这项名为化学类型进化的专利技术将应用于抗癌靶标P53-Hdm2。I/IB阶段的赠款表明，多肽可以被解构成适合进行化学型进化的诱饵。在第二阶段，化学类型进化将被用于将这些基于多肽的诱饵转化为新型的、有效的、完全非肽的P53-Hdm2相互作用抑制物。此外，通过添加额外的化学物质，这项技术的灵活性将增加。这项研究的更广泛影响是双重的。首先，发现的抑制剂可能会导致治疗癌症的新药。其次，他们的识别将验证一种可以普遍应用于困难目标的药物发现技术。将多肽转化为小分子药物的常规做法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，并为创造化学探针来研究生物途径提供一种快速且经济有效的方法。这将产生巨大的社会影响，因为这项技术将促进发现满足未得到满足的医疗需求的药物，特别是在传统技术失败的情况下。

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.