Development of Chemical Probes for Protein-Protein Interactions Inhibition

蛋白质-蛋白质相互作用（PPI）控制着与健康和疾病相关的所有细胞过程。1因此，选择性抑制单个PPI将有助于更好地理解生物学机制，并为治疗干预提供新的机会。然而，PPI抑制剂代表了当前小分子药物的一小部分，主要是因为与这些靶点的抑制剂的开发相关的特定挑战。我们团队先前的研究表明，二级结构模拟物可用于抑制与结构相关的PPIs 2，然而，小分子支架目前无法用于靶向与许多其他PPI类别相关的侧链星座。我们目前正在进行一项为期5年的主要EPSRC计划（PoPPI），重点是开发工具，以促进许多PPI类抑制剂的发现。Suzanne的博士项目将利用新的计算工具（由我们在布里斯托的合作伙伴开发）来设计，制备和评估用于选择性抑制细胞中PPI的新型小分子支架。这些小分子抑制剂的合成将利用我们开发的靶向多样化和新型铅样化学空间的合成方法。3她的主要目标将是鉴定用两个官能团修饰的通用小分子支架，这些官能团旨在模拟PPI界面处的两个热点氨基酸，从而以合理的效力与蛋白质靶点结合。专注于与肿瘤学和病毒疾病治疗相关的新型α-螺旋介导的靶点，在成功鉴定结合她选择的靶点的命中后，她将进一步阐述支架以模拟第三点并实现足够的效力来抑制PPI，从而将命中进展为化学探针开发，并证明可以鉴定通用支架以抑制蛋白质-蛋白质相互作用。实现这一目标将有助于使物理科学方法加速药物发现。Suzanne将获得以下方面的技术技能：多样性和铅导向合成;生物物理学和新型PPI受体的细胞功能评估。1.自然化学，2013，5，1612. (a)Angew.化学国际版，2015，54，2960。(b)Angew.化学国际版，2016，55，11096。3. (a)有机生物学2015，13，859;（B）Chem.Commun. 2014年，50，10222

Protein-protein interactions (PPIs) control all cellular processes relevant to health and disease.1 Selective inhibition of individual PPIs would thus facilitate both a greater understanding of biological mechanisms; and provide new opportunities for therapeutic intervention. Yet, PPI inhibitors represent a minute fraction of current small molecule drugs, largely because of specific challenges associated with development of inhibitors for these targets. Prior research in our team demonstrated that secondary structure mimetics can be used to inhibit PPIs2 related by structure, however small molecule scaffolds are currently not available to target constellations of side chains relevant to many other PPI classes. We are currently pursuing a major 5-year EPSRC programme (PoPPI) focused on developing tools to facilitate discovery of inhibitors of many PPI classes. Suzanne's PhD project will exploit new computational tools (developed by our partners in Bristol) to design, prepare and evaluate novel small molecule scaffolds for selective inhibition of PPI in cells. The synthesis of these small molecule inhibitors will exploit synthetic approaches that we have developed to target diverse and novel lead-like chemical space.3 Her key objectives will be to identify generic small-molecule scaffolds decorated with two functional groups designed to mimic two hot-spot amino acids at a PPI interface and thus bind to protein targets with reasonable potency. Focussing on novel a-helix mediated targets with therapeutic relevance to oncology and viral conditions, upon successful identification of hits that bind her selected targets, she will further elaborate the scaffolds to mimic a 3rd spot and achieve sufficient potency to inhibit the PPI thus progressing the hit towards chemical probe development and demonstrating that generic scaffolds can be identified for inhibition of protein-protein interactions. Achieving this will contribute to enabling physical sciences methodology to accelerate drug-discovery.Suzanne will gain technical skills in: diversity- and lead-oriented synthesis; and biophysics and evaluation of the cellular function of novel PPI inhibitors.1. Nature Chem., 2013, 5, 161 2. (a) Angew. Chem. Int. Ed., 2015, 54, 2960. (b) Angew. Chem. Int. Ed., 2016, 55, 11096. 3. (a) Org. Biomol. Chem. 2015, 13, 859; (b) Chem. Commun. 2014, 50, 10222