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对于提高我们对细胞过程的理解至关重要，重要的是，对于各种癌症的下一代治疗方法的开发至关重要。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。与许多参与细胞内过程的蛋白质一样，这些蛋白质通常要么完全本质无序，要么包含广泛的本质无序区域。通过操纵其内在无序区域来选择性调节其活性是一种非常有吸引力的方法，因为它避免了试图靶向与许多其他蛋白质的活性位点没有足够区别的活性位点，导致低特异性，以及试图直接干扰大的蛋白质-蛋白质界面的众所周知的问题。我们最近已经开发了用于鉴定蛋白质的内在无序区域内的独特瞬时结构化区域的新技术（Panova等人，Structure 2019 27 1-10），其可以被经典的小分子治疗剂或生物治疗剂如单克隆抗体靶向。在这项研究中，我们将在这一突破的基础上发现靶向特定转录因子和蛋白激酶的小分子和抗体，并确定在体外和体内干扰其功能的后果。我们的第一个目标将是癌基因Myc，这是我们在制药行业合作者的一个非常珍贵的癌症靶点。在博士期间，学生将获得各种技能的经验，从特异性单克隆抗体的生产和选择，体外和体内活性测定，最先进的光谱，NMR和计算方法，以确定蛋白质行为，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.