Development of anti-cancer agents and biomarkers that target intrinsically disordered regions of transcription factors and protein kinases

转录因子、蛋白激酶和蛋白磷酸酶的受控操作是提高我们对细胞过程的理解的核心，更重要的是，在开发针对各种癌症的下一代疗法方面。这些蛋白质类在制药和生物技术领域目前的药物发现组合中占很大比例。像许多参与细胞内过程的蛋白质一样，这些蛋白质通常要么是完全固有的无序的，要么包含广泛的固有无序的区域。通过操纵其固有的无序区来选择性地调节它们的活性是一种非常有吸引力的方法，因为它绕过了众所周知的问题，即试图针对与许多其他蛋白质的活性部位不够明显的活性部位，导致特异性低，并试图直接干扰大的蛋白质-蛋白质界面。我们最近开发了新的技术来识别蛋白质内在无序区域内独特的瞬时结构区域(Panova等人，Structure 2019 27 1-10)，这可以作为经典小分子疗法或生物疗法(如单抗)的靶点。在这项研究中，我们将在这一突破的基础上，发现针对特定转录因子和蛋白激酶的小分子和抗体，并确定干扰它们在体外和体内功能的后果。我们的第一个目标将是癌基因Myc，这是我们在制药行业的合作者非常珍视的癌症目标。在博士期间，学生将获得各种技能的经验，从特定的单抗生产和选择，体外和体内活性分析，最新的光谱，核磁共振和确定蛋白质行为的计算方法，结构生物学和药物筛选。

The controlled manipulation of transcription factors, protein kinases and protein phosphatases is central to improving our understanding of cellular processes and, importantly, in the development of next-generation therapeutics for a variety of cancers. These protein classes make up a large proportion of current drug discovery portfolios in the pharmaceutical and biotech sectors. Like many involved in intracellular processes, these proteins are often either entirely intrinsically disordered or contain extensive intrinsically disordered regions. The selective modulation of their activity through manipulation of their intrinsically disordered regions is a highly attractive approach since it circumvents the well-known problems of trying to target active sites that are insufficiently distinct from those of many other proteins, leading to low specificity, and trying to interfere directly with large protein-protein interfaces. We have very recently developed novel technology for the identification of unique transient structured regions within intrinsically disordered regions of proteins (Panova et al., Structure 2019 27 1-10), which can be targeted by either classical small molecule therapeutics, or by biotherapeutics, such as monoclonal antibodies. In this study, we will build on this breakthrough to discover small molecules and antibodies that target specific transcription factors and protein kinases, and determine the consequences of interfering with their function in vitro and in vivo. Our first target will be the oncogene Myc, which is a highly prized cancer target for our collaborators in the pharmaceutical industry. During the PhD, the student will gain experience in a wide variety of skills, ranging from specific monoclonal antibody production and selection, in vitro and in vivo activity assays, state-of-the-art spectroscopic, NMR and computational approaches to determining protein behaviour, structural biology and drug screening.