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

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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.