Synthesis and screening of DNA-encoded Libraries of Non-Peptidic Macrocycles

项目摘要 大多数药物靶向具有相对深口袋的蛋白质，例如酶活性位点。然而，筛选 由这些传统的符合5规则的分子组成的集合始终未能提供高的 高质量的药物导致许多通过蛋白质-核酸和蛋白质-蛋白质相互作用（PPI）发挥作用的靶点。 这些是“困难的”或“不可治疗的”蛋白质靶点，据估计，这些靶点占了蛋白质靶点的85%。 人类蛋白质组这些类型的PPI在癌症治疗等方面的重要性已得到充分注意。 近年来在感染性疾病领域，PPI在宿主和病原体之间的相互作用中发挥作用。 大环肽（MP）能够接合这些浅的、溶剂暴露的表面，但大多数MP是 不是细胞可渗透的。这突出了对开发新颖的、细胞可渗透的细胞库的迫切需要。 能够接合PPI表面的化合物。在第一阶段，我们成功地证明了 产生和筛选非肽大环化合物的大DNA编码文库，其具有适当的 特性来满足这一需求。在这个第二阶段的项目中，我们将扩大这些化学品的多样性， 文库，测试他们对几个困难的目标，并建立方法，发展初级筛选命中 转化为高质量的药物线索

Project Summary Most drugs target proteins with relatively deep pockets, such as enzyme active sites. However, screening collections comprised of these traditional Rule of 5-compliant molecules have consistently failed to provide high quality drug leads for many targets that function via protein-nucleic acid and protein-protein interactions (PPIs). These are the “difficult” or “undruggable” protein targets, which by some estimates comprise up to 85% of the human proteome. The importance of these types of PPIs has been well noted in cancer therapeutics and more recently in the infectious diseases field where PPIs play a role in the interaction between host and pathogen. Macrocyclic peptides (MPs) are capable of engaging these shallow, solvent exposed surfaces, but most MPs are not cell permeable. This highlights the critical need for the development of libraries of novel, cell permeable compounds capable of engaging PPI surfaces. In Phase I, we successfully demonstrated the feasibility of generating and screening large DNA-encoded libraries of non-peptidic macrocycles, which have the appropriate characteristics to address this need. In this Phase II project, we will expand the chemical diversity of these libraries, test them against several difficult targets, and establish methods to evolve primary screening hits derived from the libraries into high-quality drug leads.